Dihydroquinoline pyrazolyl compounds

ABSTRACT

The invention provides novel compounds having the general formula (I) 
     
       
         
         
             
             
         
       
     
     wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , m and n are as described herein, compositions including the compounds and methods of using the compounds.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation of International Application No.PCT/EP2015/074923 having an international filing date of Oct. 28, 2015and which claims benefit under 35 U.S.C. §119 to InternationalApplication PCT/CN2014/090064 filed Oct. 31, 2014. The entire contentsof both are incorporated herein by reference.

FIELD OF THE INVENTION

The present invention relates to novel compounds of formula I, asdescribed herein, having pharmaceutical activity, their manufacture,pharmaceutical compositions containing them and their potential use asmedicaments.

BACKGROUND OF THE INVENTION

Inhibitors of aldosterone synthase can potentially protect organs and/ortissues from damage caused by an absolute or relative excess ofaldosterone. Hypertension affects about 20% of the adult population indeveloped countries. In persons 60 years and older, this percentageincreases to above 60%. Hypertensive subjects display an increased riskof other physiological complications including stroke, myocardialinfarction, atrial fibrillation, heart failure, peripheral vasculardisease and renal impairment. The renin angiotensin aldosterone systemis a pathway that has been linked to hypertension, volume and saltbalance and more recently to contribute directly to end organ damage inadvanced stages of heart failure or kidney disease. ACE inhibitors andangiotensin receptor blockers (ARBs) are successfully used to improveduration and quality of life of patients. These drugs are not yieldingmaximum protection. In a relatively large number of patients ACE andARB's lead to so-called aldosterone breakthrough, a phenomenon wherealdosterone levels, after a first initial decline, return topathological levels. It has been demonstrated that the deleteriousconsequences of inappropriately increased aldosterone levels (inrelation to salt intake/levels) can be minimized by aldosterone blockadewith mineralocorticoid receptor antagonists. A direct inhibition ofaldosterone synthesis is expected to provide even better protection asit will also reduce non-genomic effects of aldosterone as well.

The effects of aldosterone on Na/K transport lead to increasedre-absorption of sodium and water and the secretion of potassium in thekidneys. Overall this results in increased blood volume and, therefore,increased blood pressure. Beyond its role in the regulation of renalsodium re-absorption aldosterone can exert deleterious effects on thekidney, the heart and the vascular system especially in a “high sodium”context. It has been shown that under such conditions aldosterone leadsto increased oxidative stress which ultimately may contribute to organdamage. Infusion of aldosterone into renally compromised rats (either byhigh salt treatment or by unilaterally nephrectomy) induces a wide arrayof injuries to the kidney including glomerular expansion, podocyteinjury, interstitial inflammation, mesangial cell proliferation andfibrosis reflected by proteinuria. More specifically aldosterone wasshown to increase the expression of the adhesion molecule ICAM-1 in thekidney. ICAM-1 is critically involved in glomerular inflammation.Similarly, aldosterone was shown to increase the expression ofinflammatory cytokines, such as interleukin IL-1b and IL-6, MCP-1 andosteopontin. On a cellular level it was demonstrated that in vascularfibroblasts aldosterone increased the expression of type I collagenmRNA, a mediator of fibrosis. Aldosterone also stimulates type IVcollagen accumulation in rat mesangial cells and induces plasminogenactivator inhibitor-1 (PAI-1) expression in smooth muscle cells. Insummary aldosterone has emerged as a key hormone involved in renaldamage. Aldosterone plays an equally important role in mediatingcardiovascular risk.

BRIEF SUMMARY OF THE INVENTION

The present invention provides novel compounds of formula (I)

wherein

-   -   R¹, R⁵, R⁶, R⁷ and R⁸ are independently selected from H, alkyl,        haloalkyl, cycloalkyl and halocycloalkyl;    -   R², R³ and R⁴ are independently selected from H, halogen, alkyl,        haloalkyl, cycloalkyl and halocycloalkyl;    -   R⁹, R¹², R¹³, R¹⁷ and R¹⁶ are independently selected from H,        alkyl and cycloalkyl;    -   R¹⁰ is alkyl, aryl, substituted aryl, arylalkyl, substituted        arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl        or substituted heteroarylalkyl, wherein substituted aryl,        substituted arylalkyl, substituted heteroaryl and substituted        heteroarylalkyl are substituted with one to three substituents        selected from alkyl, halogen, haloalkyl, cycloalkyl,        halocycloalkyl, cyano, alkoxy, haloalkoxy, alkylsulfanyl,        haloalkylsulfanyl, alkylsulfonyl and haloalkylsulfonyl;

R¹¹ and R¹⁴ together form —CH₂—CH₂—;

or R¹¹ and R¹² together form —CH₂— and R¹³ and R¹⁴ together form —CH₂—;

A is —C(O)— or —S(O)₂—

n is zero or 1;

m is 1;

and pharmaceutically acceptable salts thereof.

In another embodiment, the present inventions provide for pharmaceuticalcompositions comprising compounds of Formula I.

In another embodiment, the present invention provides aldosteronesynthase inhibitors for therapy in a mammal useful for the treatment orprophylaxis of chronic kidney disease, congestive heart failure,hypertension, primary aldosteronism and Cushing syndrome.

DETAILED DESCRIPTION OF THE INVENTION

There is ample preclinical evidence that MR-antagonists (spironolactoneand eplerenone) improve blood pressure, cardiac and renal function invarious pre-clinical models.

More recently preclinical studies highlight the important contributionof CYP11B2 to cardiovascular and renal morbidity and mortality. TheCYP11B2 inhibitor FAD286 and the MR antagonist spironolactone wereevaluated in a rat model of chronic kidney disease (high angiotensin IIexposure; high salt and uni-nephrectomy). Angiotensin II and high salttreatment caused albuminuria, azotemia, renovascular hypertrophy,glomerular injury, increased PAI-1, and osteopontin mRNA expression, aswell as tubulointerstitial fibrosis. Both drugs prevented these renaleffects and attenuated cardiac and aortic medial hypertrophy. Following4 weeks of treatment with FAD286, plasma aldosterone was reduced,whereas spironolactone increased aldosterone at 4 and 8 weeks oftreatment. Similarly only spironolactone but not FAD286 enhancedangiotensin II and salt-stimulated PAI-1 mRNA expression in the aortaand the heart. In other studies the CYP11B2 inhibitor FAD286 improvedblood pressure and cardiovascular function and structure in rats withexperimental heart failure. In the same studies FAD286 was shown toimprove kidney function and morphology.

Administration of an orally active CYP11B2 inhibitor, LCI699, topatients with primary aldosteronism, lead to the conclusion that iteffectively inhibits CYP11B2 in patients with primary aldosteronismresulting in significantly lower circulating aldosterone levels and thatit corrected the hypokalemia and mildly decreased blood pressure. Theeffects on the glucocorticoid axis were consistent with a poorselectivity of the compound and a latent inhibition of cortisolsynthesis. Taken together these data support the concept that a CYP11B2inhibitor can lower inappropriately high aldosterone levels. Achievinggood selectivity against CYP11B1 is important to be free of undesiredside effects on the HPA axis and will differentiate different CYP11B2inhibitors.

The compounds of the present invention according formula (I) are potentinhibitors of CYPB11B2 and present an improved selectivity towardsCYP11B2 versus CYP11B1 combined with an improved metabolic stability.

Objects of the present invention are the compounds of formula (I) andtheir aforementioned salts and esters and their use as therapeuticallyactive substances, a process for the manufacture of the said compounds,intermediates, pharmaceutical compositions, medicaments containing thesaid compounds, their pharmaceutically acceptable salts or esters, theuse of the said compounds, salts or esters for the treatment orprophylaxis of illnesses, especially in the treatment or prophylaxis ofchronic kidney disease, congestive heart failure, hypertension, primaryaldosteronism and Cushing syndrom and the use of the said compounds,salts or esters for the production of medicaments for the treatment orprophylaxis of chronic kidney disease, congestive heart failure,hypertension, primary aldosteronism and Cushing syndrom.

The term “alkoxy” denotes a group of the formula R′—O—, wherein R′ is analkyl group. Examples of alkoxy group include methoxy, ethoxy,n-propoxy, isopropoxy, n-butoxy, isobutoxy and tert-butoxy. Particularalkoxy group include methoxy.

The term “alkyl” denotes a monovalent linear or branched saturatedhydrocarbon group of 1 to 12 carbon atoms. In particular embodiments,alkyl has 1 to 7 carbon atoms, and in more particular embodiments 1 to 4carbon atoms. Examples of alkyl include methyl, ethyl, propyl andisopropyl, n-butyl, iso-butyl, sec-butyl and ter-butyl. Particular alkylgroups are methyl and ethyl.

The term “alkylsulfanyl” denotes a group of the formula R′—S—, whereinR′ is an alkyl group. Examples of alkylsulfanyl are groups wherein R′ ismethyl, ethyl, propyl and isopropyl, n-butyl, iso-butyl, sec-butyl andter-butyl. Particular alkylsulfanyl is group wherein R′ is methyl.

The term “alkylsulfonyl” denotes a group of the formula R′—S(O)₂—,wherein R′ is an alkyl group. Examples of alkylsulfonyl are groupswherein R′ is methyl, ethyl, propyl and isopropyl, n-butyl, iso-butyl,sec-butyl and ter-butyl. Particular alkylsulfonyl is group wherein R′ ismethyl.

The term “aryl” denotes a monovalent aromatic carbocyclic mono- orbicyclic ring system comprising 6 to 10 carbon ring atoms. Examples ofaryl moieties include phenyl and naphthyl. Particular aryl group isphenyl.

The term “arylalkyl” denotes an alkyl group wherein one of the hydrogenatoms of the alkyl group has been replaced an aryl group. Particulararylalkyl group is phenylmethyl.

The term “cyano” denotes a —C≡N group.

The term “cycloalkyl” denotes a monovalent saturated monocyclichydrocarbon group of 3 to 10 ring carbon atoms. In particularembodiments, cycloalkyl denotes a monovalent saturated monocyclichydrocarbon group of 3 to 8 ring carbon atoms. Examples for cycloalkylare cyclopropyl, cyclobutanyl, cyclopentyl, cyclohexyl or cycloheptyl.Particular cycloalkyl group is cyclopropyl.

The term “haloalkoxy” denotes an alkoxy group wherein at least one ofthe hydrogen atoms of the alkoxy group has been replaced by same ordifferent halogen atoms. The term “perhaloalkoxy” denotes an alkoxygroup where all hydrogen atoms of the alkoxy group have been replaced bythe same or different halogen atoms. Examples of haloalkoxy includefluoromethoxy, difluoromethoxy, trifluoromethoxy, trifluoroethoxy,trifluoromethylethoxy, trifluorodimethylethoxy and pentafluoroethoxy.

The term “haloalkyl” denotes an alkyl group wherein at least one of thehydrogen atoms of the alkyl group has been replaced by the same ordifferent halogen atoms. The term “perhaloalkyl” denotes an alkyl groupwhere all hydrogen atoms of the alkyl group have been replaced by thesame or different halogen atoms. Examples of haloalkyl includefluoromethyl, difluoromethyl, trifluoromethyl, trifluoroethyl,trifluoromethylethyl and pentafluoroethyl. Particular haloalkyl group istrifluoromethyl.

The term “haloalkylsulfanyl” denotes a group of the formula —S—R′,wherein R′ is a haloalkyl group. Examples of haloalkylsulfanyl groupsinclude groups of the formula —S—R′, wherein R′ is trifluoromethyl.

The term “haloalkylsulfonyl” denotes a group of the formula —S(O)₂—R′,wherein R′ is a haloalkyl group. Examples of haloalkylsulfonyl groupsinclude groups of the formula —S(O)₂—R′, wherein R′ is trifluoromethyl.

The term “halocycloalkyl” denotes a cycloalkyl group wherein at leastone of the hydrogen atoms of the cycloalkyl group has been replaced bysame or different halogen atoms, particularly fluoro atoms. Examples ofhalocycloalkyl include fluorocyclopropyl, difluorocyclopropyl,fluorocyclobutyl and difluorocyclobutyl.

The term “halogen” and “halo” are used interchangeably herein and denotefluoro, chloro, bromo, or iodo. Particular halogens are chloro andfluoro. Particular halogen is fluoro.

The term “heteroaryl” denotes a monovalent aromatic heterocyclic mono-or bicyclic ring system of 5 to 12 ring atoms, comprising 1, 2, 3 or 4heteroatoms selected from N, O and S, the remaining ring atoms beingcarbon. Examples of heteroaryl include pyrrolyl, furanyl, thienyl,imidazolyl, oxazolyl, thiazolyl, triazolyl, oxadiazolyl, thiadiazolyl,tetrazolyl, pyridinyl, pyrazinyl, pyrazolyl, pyridazinyl, pyrimidinyl,triazinyl, azepinyl, diazepinyl, isoxazolyl, benzofuranyl, isothiazolyl,benzothienyl, indolyl, isoindolyl, isobenzofuranyl, benzimidazolyl,benzoxazolyl, benzoisoxazolyl, benzothiazolyl, benzoisothiazolyl,benzooxadiazolyl, benzothiadiazolyl, benzotriazolyl, purinyl,quinolinyl, isoquinolinyl, quinazolinyl and quinoxalinyl. Particularheteroaryl are imidazolyl, pyridinyl and pyrazolyl.

The term “heteroarylalkyl” denotes an alkyl group wherein one of thehydrogen atoms of the alkyl group has been replaced an aryl group.Particular heteroarylalkyl group is heteroarylmethyl.

The term “pharmaceutically acceptable salts” refers to those salts whichretain the biological effectiveness and properties of the free bases orfree acids, which are not biologically or otherwise undesirable. Thesalts are formed with inorganic acids such as hydrochloric acid,hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and thelike, in particular hydrochloric acid, and organic acids such as aceticacid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleicacid, malonic acid, succinic acid, fumaric acid, tartaric acid, citricacid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid,ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid,N-acetylcystein and the like. In addition these salts may be prepared byaddition of an inorganic base or an organic base to the free acid. Saltsderived from an inorganic base include, but are not limited to, thesodium, potassium, lithium, ammonium, calcium, magnesium salts and thelike. Salts derived from organic bases include, but are not limited tosalts of primary, secondary, and tertiary amines, substituted aminesincluding naturally occurring substituted amines, cyclic amines andbasic ion exchange resins, such as isopropylamine, trimethylamine,diethylamine, triethylamine, tripropylamine, ethanolamine, lysine,arginine, N-ethylpiperidine, piperidine, polyimine resins and the like.Particular pharmaceutically acceptable salts of compounds of formula (I)are the hydrochloride salts, methanesulfonic acid salts and citric acidsalts.

“Pharmaceutically acceptable esters” means that compounds of generalformula (I) may be derivatised at functional groups to providederivatives which are capable of conversion back to the parent compoundsin vivo. Examples of such compounds include physiologically acceptableand metabolically labile ester derivatives, such as methoxymethylesters, methylthiomethyl esters and pivaloyloxymethyl esters.μAdditionally, any physiologically acceptable equivalents of thecompounds of general formula (I), similar to the metabolically labileesters, which are capable of producing the parent compounds of generalformula (I) in vivo, are within the scope of this invention.

The term “protecting group” (PG) denotes the group which selectivelyblocks a reactive site in a multifunctional compound such that achemical reaction can be carried out selectively at another unprotectedreactive site in the meaning conventionally associated with it insynthetic chemistry. Protecting groups can be removed at the appropriatepoint. Exemplary protecting groups are amino-protecting groups,carboxy-protecting groups or hydroxy-protecting groups. Particularprotecting groups are the tert-butoxycarbonyl (Boc), benzyloxycarbonyl(Cbz), fluorenylmethoxycarbonyl (Fmoc) and benzyl (Bn). Furtherparticular protecting groups are the tert-butoxycarbonyl (Boc) and thefluorenylmethoxycarbonyl (Fmoc). More particular protecting group is thetert-butoxycarbonyl (Boc).

The abbreviation uM means microMolar and is equivalent to the symbol μM.

The compounds of the present invention can also contain unnaturalproportions of atomic isotopes at one or more of the atoms thatconstitute such compounds. For example, the present invention alsoembraces isotopically-labeled variants of the present invention whichare identical to those recited herein, but for the fact that one or moreatoms are replaced by an atom having the atomic mass or mass numberdifferent from the predominant atomic mass or mass number usually foundin nature for the atom. All isotopes of any particular atom or elementas specified are contemplated within the scope of the compounds of theinvention, and their uses. Exemplary isotopes that can be incorporatedin to compounds of the invention include isotopes of hydrogen, carbon,nitrogen, oxygen, phosphorous, sulfur, fluorine, chlorine and iodine,such as ²H (“D”), ³H (“T”), ¹¹C, ¹³C, ¹⁴C, ¹³N, ¹⁵N, ¹⁵O, ¹⁷O, ¹⁸O, ³²P,³³P, ³⁵S, ¹⁸F, ³⁶Cl, ¹²³I, and ¹²⁵I. Certain isotopically labeledcompounds of the present invention (e.g., those labeled with ³H or ¹⁴C)are useful in compound and/or substrate tissue distribution assays.Tritiated (³H) and carbon-14 (¹⁴C) isotopes are useful for their ease ofpreparation and detectability. Further substitution with heavierisotopes such as deuterium (i.e., ²H) may afford certain therapeuticadvantages resulting from greater metabolic stability (e.g., increasedin vivo half-life or reduced dosage requirements) and hence may bepreferred in some circumstances. Positron emitting isotopes such as ¹⁵O,¹³N, ¹¹C and ¹⁸F are useful for positron emission tomography (PET)studies to examine substrate receptor occupancy. Isotopically labeledcompounds of the present inventions can generally be prepared byfollowing procedures analogous to those disclosed in the Schemes and/orin the Examples herein below, by substituting a non-isotopically labeledreagent with a isotopically labeled reagent. In particular, compounds offormula (I) wherein one or more H atom have been replaced by a ²H atomare also an embodiment of this invention.

The compounds of formula (I) can contain several asymmetric centers andcan be present in the form of optically pure enantiomers, mixtures ofenantiomers such as, for example, racemates, optically purediastereoisomers, mixtures of diastereoisomers, diastereoisomericracemates or mixtures of diastereoisomeric racemates.

According to the Cahn-Ingold-Prelog Convention the asymmetric carbonatom can be of the “R” or “S” configuration.

Also an embodiment of the present invention are compounds according toformula (I) as described herein and pharmaceutically acceptable salts oresters thereof, in particular compounds according to formula (I) asdescribed herein and pharmaceutically acceptable salts thereof, moreparticularly compounds according to formula (I) as described herein.

Also a particular embodiment of the present invention are compoundsaccording to formula (I) as described herein wherein R¹ is alkyl.

Also a further particular embodiment of the present invention arecompounds according to formula (I) as described herein wherein R¹ ismethyl.

A particular embodiment of the present invention are compounds accordingto formula (I) as described herein, wherein R⁵, R⁶, R⁷ and R⁸ are H.

Another particular embodiment of the present invention are compoundsaccording to formula (I) as described herein, wherein R² is H.

Also an embodiment of the present invention are compounds according toformula (I) as described herein, wherein one of R³ and R⁴ is H and theother one is halogen.

A more particular embodiment of the present invention are compoundsaccording to formula (I) as described herein, wherein R³ and R⁴ are H.

Another particular embodiment of the present invention are compoundsaccording to formula (I) as described herein, wherein R¹⁶ is H or alkyl.

Also a particular embodiment of the present invention are compoundsaccording to formula (I) as described herein, wherein R⁹, R¹², R¹³, andR¹⁷ are H.

Another embodiment of the present invention are compounds according toformula (I) as described herein, wherein R⁹, R¹², R¹³, R¹⁶ and R¹⁷ areH.

Another particular embodiment of the present invention are compoundsaccording to formula (I) as described herein, wherein n is 1.

Another embodiment of the present invention are compounds according toformula (I) as described herein, wherein A is —C(O)—.

Another particular embodiment of the present invention are compounds offormula (I) as described above wherein R⁹, R¹², R¹³, R¹⁶ and R¹⁷ in eachoccurrence are independently selected from H, alkyl and cycloalkyl, and,R¹² together with R¹⁴ form —CH₂CH₂—.

Another particular embodiment of the present invention are compounds offormula (I) as described above wherein R⁹, R¹⁶ and R¹⁷ in eachoccurrence are independently selected from H, alkyl and cycloalkyl andR¹² together with R¹¹ and R¹³ together with R¹⁴ both form —CH₂—.

A particular embodiment of the present invention are compounds accordingto formula (I) as described herein, wherein R¹⁰ is alkyl or heteroarylsubstituted with one to three substituents selected from alkyl, halogen,cyano, alkoxy, alkylsulfanyl and alkylsulfonyl.

A further particular embodiment of the present invention are compoundsaccording to formula (I) as described herein, wherein R¹⁰ is alkyl orsubstituted pyrazolyl, substituted imidazolyl or substituted pyridinyl,wherein substituted pyrazolyl, substituted imidazolyl and substitutedpyridinyl are substituted with one to three substituents selected fromalkyl, halogen, cyano, alkoxy, alkylsulfanyl and alkylsulfonyl.

A more particular embodiment of the present invention are compoundsaccording to formula (I) as described herein, wherein R¹⁰ is alkyl orsubstituted pyrazolyl, substituted imidazolyl or substituted pyridinyl,wherein substituted pyrazolyl, substituted imidazolyl and substitutedpyridinyl are substituted with one alkyl or one halogen.

A further more particular embodiment of the present invention arecompounds according to formula (I) as described herein, wherein R¹⁰ issubstituted pyrazolyl, substituted imidazolyl or substituted pyridinyl,wherein substituted pyrazolyl, substituted imidazolyl and substitutedpyridinyl are substituted with one alkyl or one halogen.

A even more particular embodiment of the present invention are compoundsaccording to formula (I) as described herein, wherein R¹⁰ ismethylpyrazolyl, methylimidazolyl or chloropyridinyl.

Particular examples of compounds of formula (I) as described herein areselected from

-   6-[4-[(1-Acetyl-4-piperidyl)methyl]-1H-pyrazol-3-yl]-1-methyl-3,4-dihydroquinolin-2-one;-   1-Methyl-6-[4-[[1-(1-methylpyrazole-4-carbonyl)-4-piperidyl]methyl]-1H-pyrazol-3-yl]-3,4-dihydroquinolin-2-one;-   6-[4-[(1-Ethylsulfonyl-4-piperidyl)methyl]-1H-pyrazol-3-yl]-1-methyl-3,4-dihydroquinolin-2-one;-   6-[4-[(1-Acetylpiperidin-4-yl)methyl]-1H-pyrazol-3-yl]-7-fluoro-1-methyl-3,4-dihydroquinolin-2-one;-   5-Fluoro-1-methyl-6-[4-[[1-(1-methylpyrazole-4-carbonyl)piperidin-4-yl]methyl]-1H-pyrazol-3-yl]-3,4-dihydroquinolin-2-one;-   6-[4-[(1-Acetylpiperidin-4-yl)methyl]-1H-pyrazol-3-yl]-5-fluoro-1-methyl-3,4-dihydroquinolin-2-one;-   6-[4-[(1-Ethylsulfonylpiperidin-4-yl)methyl]-1H-pyrazol-3-yl]-5-fluoro-1-methyl-3,4-dihydroquinolin-2-one;-   5-Fluoro-1-methyl-6-[4-[[1-(2-methylpyrazole-3-carbonyl)piperidin-4-yl]methyl]-1H-pyrazol-3-yl]-3,4-dihydroquinolin-2-one;-   5-Fluoro-1-methyl-6-[4-[[1-(1-methylimidazole-2-carbonyl)piperidin-4-yl]methyl]-1H-pyrazol-3-yl]-3,4-dihydroquinolin-2-one;-   6-[4-[(1-Acetylpiperidin-4-yl)methyl]-1H-pyrazol-3-yl]-5-chloro-1-methyl-3,4-dihydroquinolin-2-one;-   1-Methyl-6-[4-[[1-(2-methylpyrazole-3-carbonyl)-4-piperidyl]methyl]-1H-pyrazol-3-yl]-3,4-dihydroquinolin-2-one;-   5-Chloro-1-methyl-6-[4-[[1-(1-methylpyrazole-4-carbonyl)-4-piperidyl]methyl]-1H-pyrazol-3-yl]-3,4-dihydroquinolin-2-one;-   5-Chloro-6-[4-[[1-(3-chloropyridine-2-carbonyl)-4-piperidyl]methyl]-1H-pyrazol-3-yl]-1-methyl-3,4-dihydroquinolin-2-one;-   5-Chloro-1-methyl-6-[4-[[1-(2-methylpyrazole-3-carbonyl)-4-piperidyl]methyl]-1H-pyrazol-3-yl]-3,4-dihydroquinolin-2-one;-   5-Chloro-6-[4-[[1-(3-chloropyridine-4-carbonyl)-4-piperidyl]methyl]-1H-pyrazol-3-yl]-1-methyl-3,4-dihydroquinolin-2-one;-   1-Methyl-6-[4-[[1-(3-methylimidazole-4-carbonyl)-4-piperidyl]methyl]-1H-pyrazol-3-yl]-3,4-dihydroquinolin-2-one;-   1-Methyl-6-[4-[[1-(1-methylimidazole-2-carbonyl)-4-piperidyl]methyl]-1H-pyrazol-3-yl]-3,4-dihydroquinolin-2-one;-   1-Methyl-6-[4-[[1-(4-methylpyridine-3-carbonyl)-4-piperidyl]methyl]-1H-pyrazol-3-yl]-3,4-dihydroquinolin-2-one;-   6-[4-[[1-(3-Chloropyridine-2-carbonyl)-4-piperidyl]methyl]-1H-pyrazol-3-yl]-1-methyl-3,4-dihydroquinolin-2-one;-   (rac)-6-[4-[1-(1-Acetylpiperidin-4-yl)ethyl]-1H-pyrazol-3-yl]-7-fluoro-1-methyl-3,4-dihydroquinolin-2-one;-   (rac)-6-[4-[1-(1-Acetylpiperidin-4-yl)ethyl]-1H-pyrazol-3-yl]-5-fluoro-1-methyl-3,4-dihydroquinolin-2-one;-   6-[4-[(1S or    1R)-1-(1-Acetylpiperidin-4-yl)ethyl]-1H-pyrazol-3-yl]-5-fluoro-1-methyl-3,4-dihydroquinolin-2-one;-   6-[4-[(1R or    1S)-1-(1-Acetylpiperidin-4-yl)ethyl]-1H-pyrazol-3-yl]-5-fluoro-1-methyl-3,4-dihydroquinolin-2-one;-   5-Chloro-6-[4-[(2-ethylsulfonyl-2-azaspiro[3.3]heptan-6-yl)methyl]-1H-pyrazol-3-yl]-1-methyl-3,4-dihydroquinolin-2-one;-   6-[4-[(2-Acetyl-2-azaspiro[3.3]heptan-6-yl)methyl]-1H-pyrazol-3-yl]-5-chloro-1-methyl-3,4-dihydroquinolin-2-one;-   5-Chloro-1-methyl-6-[4-[[2-(1-methylpyrazole-4-carbonyl)-2-azaspiro[3.3]heptan-6-yl]methyl]-1H-pyrazol-3-yl]-3,4-dihydroquinolin-2-one;

and pharmaceutically acceptable salts thereof.

Processes for the manufacture of compounds of formula (I) as describedherein are an object of the invention.

The preparation of compounds of formula (I) of the present invention maybe carried out in sequential or convergent synthetic routes. Synthesesof the invention are shown in the following general schemes. The skillsrequired for carrying out the reaction and purification of the resultingproducts are known to those persons skilled in the art. In case amixture of enantiomers or diastereoisomers is produced during areaction, these enantiomers or diastereoisomers can be separated bymethods described herein or known to the persons skilled in the art suchas e.g. chiral chromatography or crystallization. The substituents andindices used in the following description of the processes have thesignificance given herein.

The following abbreviations are used in the present text:

AcOH=acetic acid, BOC=t-butyloxycarbonyl, BuLi=butyllithium,CDI=1,1-carbonyldiimidazole, DCM=dichloromethane,DBU=2,3,4,6,7,8,9,10-octahydro-pyrimido[1,2-a]azepine,DCE=1,2-dichloroethane, DIBALH=di-i-butylaluminium hydride,DCC=N,N′-dicyclohexylcarbodiimide, DMA=N,N-dimethylacetamide,DMAP=4-dimethylaminopyridine, DMF=N,N-dimethylformamide,EDCI=N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride,EtOAc=ethylacetate, EtOH=ethanol, Et₂O=diethylether, Et₃N=triethylamine,eq=equivalents,HATU=O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluroniumhexafluorophosphate, HPLC=high performance liquid chromatography,HOBT=1-hydroxybenzo-triazole, Huenig's base=iPr₂NEt=N-ethyldiisopropylamine, IPC=in process control, LAH=lithium aluminium hydride,LDA=lithium diisopropylamide, LiBH₄=lithium borohydride, MeOH=methanol,NaBH₃CN, sodium cyanoborohydride, NaBH₄=sodium borohydride, NaI=sodiumiodide, Red-Al=sodium bis(2-methoxyethoxy) aluminium hydride, RT=roomtemperature, TBDMSCl=t-butyldimethylsilyl chloride, TFA=trifluoroaceticacid, THF=tetrahydrofuran, quant=quantitative.

Prot.=Protecting Group

X is Halogen or OSO₂CF₃

R¹⁰¹ and R¹⁰² are both OH or, e.g. together with the boron atom to whichthey are attached form

R¹⁰⁵ stands for

Halo-pyrazoles 101 preferably with X equal bromine or iodine, andcarrying a suitable protecting group at the pyrazole nitrogen atom canundergo halogen-metal exchange when treated with metals like magnesiumor lithium in solvents like tetrahydrofuran in a temperature rangebetween −78° C. and 0° C. and react subsequently with aldehydes orketones 102 to adducts 103 preferably in a temperature range between−78° C. and room temperature (Scheme 3, step a). Hydroxy groups incompounds 103 can be removed and replaced by hydrogen by treatment e.g.with a reagent like triethylsilane in a solvent like trifluoroaceticacid preferably between 0° C. and room temperature or a carbonsubstituent with a reagent like an optionally substitutedallyl-trimethylsilane in the presence of a catalyst like bismuth(III)chloride in solvents like dichloromethane around room temperature givingsubstituted pyrazoles 104 (step b), a double bond in the newlyintroduced carbon substituent can subsequently be reduced by catalytichydrogenation. Halogenation, e.g. iodination or bromination of compounds104 using e.g. ICl in acetic acid or N-iodo or N-bromo succinimide insolvents like acetonitrile in a temperature range between 0° C. and thereflux temperature of the solvents gives halo-pyrazoles 105 (step c).Condensation of halo-pyrazoles 105 with boronic acid or ester compounds106 (known in the art or being prepared as described in Schemes 5 and 6)can be performed using Suzuki conditions, e.g. in the presence ofcatalysts, such as tri-o-tolylphosphine/palladium(II)acetate,tetrakis-(triphenylphosphine)-palladium,bis(triphenylphosphine)palladium(II)chloride ordichloro[1,1′-bis(diphenylphosphino)-ferrocene]palladium(II) optionallyin the form of a dichloromethane complex (1:1), and in the presence of abase, such as aqueous or non aqueous potassium phosphate, sodium orpotassium carbonate, in a solvent, such as dimethylsulfoxide, toluene,ethanol, dioxane, tetrahydrofuran or N,N-dimethylformamide, and in aninert atmosphere such as argon or nitrogen, in a temperature rangepreferably between room temperature and about 130° C. leading topyrazoles 107 (steps d). Removal of the protecting group in pyrazoles107 then leads to pyrazoles 108 (e.g. treatment with trifluoroaceticacid under microwave conditions at temperatures around 100° C. can beused for removal of a p-methoxy-benzyl protecting group, treatment with4M HCl in dioxane in MeOH around room temperature can be used forremoval of a THP protecting group) (steps e).

R¹⁰¹ and R¹⁰² are both OH or, e.g. together with the boron atom to whichthey are attached form

Chloropropionic acid anilides 201 (Scheme 5) can be prepared from chloropropionic acid chlorides and anilines 200 by reaction in a solvent likeDCM in the presence of a base like pyridine preferably around roomtemperature (step a). Chloropropionic acid anilides 201 undergo ringclosure to lactam compounds 202 when treated with AlCl₃ preferablywithout solvent at elevated temperatures of e.g. 100 to 150° C. (stepb). Lactam compounds 202 can be alkylated at nitrogen using a base likesodium hydride or sodium or potassium tert-butoxide, followed byaddition of an alkylating agent of formula R¹—Y wherein Y is halogen,tosylate or mesylate, in a solvent like DMF or THF preferably in atemperature range between 0° C. and about 80° C. giving N-alkylatedlactams 203 (step c). Optional halogenation of N-alkylated lactams 203can be performed e.g. by using N-bromo or N-chloro succinimide insolvents like DMF preferably around room temperature giving halo lactamcompounds 204 with X equal to bromine or chlorine respectively (step d).Reaction of lactams 204 with e.g.4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) in solventslike dimethylsulfoxide or dioxane in the presence of potassium acetateand catalysts like(1,1′-bis-diphenylphosphino)-ferrocene)palladium-(II)dichloride (1:1complex with dichloromethane) at temperatures up to about 100° C. givesboronic ester compounds 106 (step e).

R¹⁰¹ and R¹⁰² are both OH or, e.g. together with the boron atom to whichthey are attached form

Treatment of nitro-benzene derivatives 250 e.g. with N-bromosuccinimide, benzoyl peroxide (BPO) in a solvent like CCl₄ preferably atreflux gives bromo-methyl compounds 251 (Scheme 6, step a). Reaction ofbromo-methyl compounds 251 and a suitable malonic ester derivative,preferable in the presence of cesium carbonate in a solvent like DMFbetween 0° C. and room temperature gives malonic ester adducts 252 (stepb). Reduction of the nitro malonic ester derivatives 252 with e.g.stannous chloride dihydrate in 6 M aq. HCl at elevated temperature (e.g.130° C.) directly leads to lactam compounds 253 (step c). Lactamcompounds 253 can be alkylated at nitrogen, halogenated and convertedinto boronic ester compounds 256 as described for the preparation ofcompounds 106 (Scheme 5) (steps d, e, f).

Also an embodiment of the present invention is a process to prepare acompound of formula (I) as defined above comprising the reaction of acompound of formula (II) in the presence of a compound of formula (III);

wherein R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹², R¹³, R¹⁴,R¹⁵, R¹⁶, R¹⁷, m and n are described herein and X is halogen or hydroxy.

In particular, in the presence of a base, in particular triethylamine,in a solvent, in particular in dichloromethane, optionally in thepresence of a coupling agent, in particular HATU, and at temperaturebetween about −20° C. and the room temperature.

Also an object of the present invention is a compound according toformula (I) as described herein for use as therapeutically activesubstance.

Likewise an object of the present invention is a pharmaceuticalcomposition comprising a compound according to formula (I) as describedherein and a therapeutically inert carrier.

The present invention also relates to the use of a compound according toformula (I) as described herein for the treatment or prophylaxis ofchronic kidney disease, congestive heart failure, hypertension, primaryaldosteronism and Cushing syndrom.

The present invention also relates to the use of a compound according toformula (I) as described herein for the treatment or prophylaxis ofdiabetic nephropathy.

The present invention also relates to the use of a compound according toformula (I) as described herein for the treatment or prophylaxis ofkidney or heart fibrosis.

The present invention also relates to the use of a compound according toformula (I) as described herein for the treatment or prophylaxis ofchronic kidney disease.

The present invention also relates to the use of a compound according toformula (I) as described herein for the treatment or prophylaxis ofcongestive heart failure.

The present invention also relates to the use of a compound according toformula (I) as described herein for the treatment or prophylaxis ofhypertension.

The present invention also relates to the use of a compound according toformula (I) as described herein for the treatment or prophylaxis ofprimary aldosteronism.

A particular embodiment of the present invention is a compound accordingto formula (I) as described herein for the treatment or prophylaxis ofchronic kidney disease, congestive heart failure, hypertension, primaryaldosteronism and Cushing syndrom.

Also a particular embodiment of the present invention is a compoundaccording to formula (I) as described herein for the treatment orprophylaxis of diabetic nephropathy.

Another particular embodiment of the present invention is a compoundaccording to formula (I) as described herein for the treatment orprophylaxis of kidney or heart fibrosis.

Also a particular embodiment of the present invention is a compoundaccording to formula (I) as described herein for the treatment orprophylaxis of chronic kidney disease.

Also a particular embodiment of the present invention is a compoundaccording to formula (I) as described herein for the treatment orprophylaxis of congestive heart failure.

Also a particular embodiment of the present invention is a compoundaccording to formula (I) as described herein for the treatment orprophylaxis of hypertension.

Also a particular embodiment of the present invention is a compoundaccording to formula (I) as described herein for the treatment orprophylaxis of primary aldosteronism.

The present invention also relates to the use of a compound according toformula (I) as described herein for the preparation of a medicament forthe treatment or prophylaxis of chronic kidney disease, congestive heartfailure, hypertension, primary aldosteronism and Cushing syndrom.

The present invention also relates to the use of a compound according toformula (I) as described herein for the preparation of a medicament forthe treatment or prophylaxis of diabetic nephropathy.

The present invention also relates to the use of a compound according toformula (I) as described herein for the preparation of a medicament forthe treatment or prophylaxis of kidney or heart fibrosis.

Also an embodiment of the present invention is the use of a compoundaccording to formula (I) as described herein for the preparation of amedicament for the treatment or prophylaxis of chronic kidney disease.

Also an embodiment of the present invention is the use of a compoundaccording to formula (I) as described herein for the preparation of amedicament for the treatment or prophylaxis of congestive heart failure.

Also an embodiment of the present invention is the use of a compoundaccording to formula (I) as described herein for the preparation of amedicament for the treatment or prophylaxis of hypertension.

Also an embodiment of the present invention is the use of a compoundaccording to formula (I) as described herein for the preparation of amedicament for the treatment or prophylaxis of primary aldosteronism.

Also an object of the invention is a method for the treatment orprophylaxis of chronic kidney disease, congestive heart failure,hypertension, primary aldosteronism and Cushing syndrom, which methodcomprises administering an effective amount of a compound according toformula (I) as described herein.

Also an object of the invention is a method for the treatment orprophylaxis of diabetic nephropathy, which method comprisesadministering an effective amount of a compound according to formula (I)as described herein.

Also an object of the invention is a method for the treatment orprophylaxis of kidney or heart fibrosis, which method comprisesadministering an effective amount of a compound according to formula (I)as described herein.

Also an embodiment of the present invention is a method for thetreatment or prophylaxis of chronic kidney disease, which methodcomprises administering an effective amount of a compound according toformula (I) as described herein.

Also an embodiment of the present invention is a method for thetreatment or prophylaxis of congestive heart failure, which methodcomprises administering an effective amount of a compound according toformula (I) as described herein.

Also an embodiment of the present invention is a method for thetreatment or prophylaxis of hypertension, which method comprisesadministering an effective amount of a compound according to formula (I)as described herein.

Also an embodiment of the present invention is a method for thetreatment or prophylaxis of primary aldosteronism, which methodcomprises administering an effective amount of a compound according toformula (I) as described herein.

Also an embodiment of the present invention is a compound of formula (I)as described herein, when manufactured according to any one of thedescribed processes.

Assay Procedures

Herein we identified the use of the G-402 cell line as a host cell toectopically express (transiently or stably) enzymes of the CYP11 family.Specifically we developed stable G-402 cells expressing ectopicallyhuman CYP11B1, human CYP11B2, human CYP11A1, cynmolgus CYP11B1 orcynomolgus CYP11B2 enzyme activity. Importantly the identified cell lineG-402 expresses co-factors (adrenodoxin and adrenodoxin reductase)important for the activity of the CYP11 family and no relevant enzymeactivity of the CYP11 family (in comparison to H295R cells) was detectedin these cells. Therefore the G-402 cell line is uniquely suited as ahost cell for the ectopic expression of enzymes from the CYP11 family.

G-402 cells can be obtained from ATCC (CRL-1440) and were originallyderived from a renal leiomyoblastoma.

The expression plasmids contains the ORF for either human/cyno CYP11B1or CYP11B2 under the control of a suitable promoter (CMV-promoter) and asuitable resistance marker (neomycin). Using standard techniques theexpression plasmid is transfected into G-402 cells and these cells arethen selected for expressing the given resistance markers. Individualcell-clones are then selected and assessed for displaying the desiredenzymatic activity using 11-Deoxycorticosterone (Cyp11B2) or11-Deoxycortisol (Cyp11B1) as a substrate.

G-402 cells expressing CYP11 constructs were established as describedabove and maintained in McCoy's 5a Medium Modified, ATCC Catalog No.30-2007 containing 10% FCS and 400 μg/ml G418 (Geneticin) at 37° C.under an atmosphere of 5% CO2/95% air. Cellular enzyme assays wereperformed in DMEM/F12 medium containing 2.5% charcoal treated FCS andappropriate concentration of substrate (0.3-10 uM11-Deoxycorticosterone, 11-Deoxycortisol or Corticosterone). Forassaying enzymatic activity, cells were plated onto 96 well plates andincubated for 16 h. An aliquot of the supernatant is then transferredand analyzed for the concentration of the expected product (Aldosteronefor CYP11B2; Cortisol for CYP11B1). The concentrations of these steroidscan be determined using HTRF assays from CisBio analyzing eitherAldosterone or Cortisol.

Inhibition of the release of produced steroids can be used as a measureof the respective enzyme inhibition by test compounds added during thecellular enzyme assay. The dose dependent inhibition of enzymaticactivity by a compound is calculated by means of plotting addedinhibitor concentrations (x-axes) vs. measured steroid/product level(y-axes). The inhibition is then calculated by fitting the following4-parameter sigmoidal function (Morgan-Mercer-Flodin (MMF) model) to theraw data points using the least squares method:

$y = \frac{{AB} + {Cx}^{D}}{B + x^{D}}$

wherein, A is the maximum y value, B is the EC50 factor determined usingXLFit, C is the minimum y value and D is the slope value.

The maximum value A corresponds to the amount of steroid produced in theabsence of an inhibitor, the value C corresponds to the amount ofsteroid detected when the enzyme is fully inhibited.

EC50 values for compounds claimed herein were tested with the G402-basedassay system described. Cyp11B2 enzyme activity was tested in presenceof 1 μM Deoxycorticosterone and variable amounts of inhibitors; Cyp11B1enzyme activity was tested in presence of 1 μM Deoxycortisol andvariable amounts of inhibitors.

EC50 EC50 human human CYP11B2 CYP11B1 Example nM nM 16 0.0283 0.2661 170.0066 1.2009 18 0.0052 0.2165 19 0.0171 0.4157 20 0.0049 0.7228 210.012 0.4474 22 0.0018 0.1332 23 0.0136 0.7039 24 0.008 0.0762 25 0.0080.184 26 0.0204 0.8434 27 0.0024 0.4988 28 0.0276 2.4474 29 0.01643.3124 30 0.0192 2.4654 31 0.007 1.1228 32 0.0294 0.3512 33 0.00661.3004 34 0.0145 0.5469 35 0.0051 0.067 36 0.0034 0.0485 37 0.06424.5814 38 0.0124 0.074 39 0.0059 0.2146 40 0.0495 2.4723 41 0.03777.2904

Compounds of formula (I) and their pharmaceutically acceptable salts oresters thereof as described herein have EC₅₀ (CYP11B2) values between0.000001 uM and 1000 uM, particular compounds have EC₅₀ (CYP11B2) valuesbetween 0.00005 uM and 500 uM, further particular compounds have EC₅₀(CYP11B2) values between 0.0005 uM and 50 uM, more particular compoundshave EC₅₀ (CYP11B2) values between 0.0005 uM and 5 uM. These resultshave been obtained by using the described enzymatic assay.

The compounds of formula (I) and their pharmaceutically acceptable saltscan be used as medicaments (e.g. in the form of pharmaceuticalpreparations). The pharmaceutical preparations can be administeredinternally, such as orally (e.g. in the form of tablets, coated tablets,dragées, hard and soft gelatin capsules, solutions, emulsions orsuspensions), nasally (e.g. in the form of nasal sprays) or rectally(e.g. in the form of suppositories). However, the administration canalso be effected parentally, such as intramuscularly or intravenously(e.g. in the form of injection solutions).

The compounds of formula (I) and their pharmaceutically acceptable saltscan be processed with pharmaceutically inert, inorganic or organicadjuvants for the production of tablets, coated tablets, dragées andhard gelatin capsules. Lactose, corn starch or derivatives thereof,talc, stearic acid or its salts etc. can be used, for example, as suchadjuvants for tablets, dragées and hard gelatin capsules.

Suitable adjuvants for soft gelatin capsules, are, for example,vegetable oils, waxes, fats, semi-solid substances and liquid polyols,etc.

Suitable adjuvants for the production of solutions and syrups are, forexample, water, polyols, saccharose, invert sugar, glucose, etc.

Suitable adjuvants for injection solutions are, for example, water,alcohols, polyols, glycerol, vegetable oils, etc.

Suitable adjuvants for suppositories are, for example, natural orhardened oils, waxes, fats, semi-solid or liquid polyols, etc.

Moreover, the pharmaceutical preparations can contain preservatives,solubilizers, viscosity-increasing substances, stabilizers, wettingagents, emulsifiers, sweeteners, colorants, flavorants, salts forvarying the osmotic pressure, buffers, masking agents or antioxidants.They can also contain still other therapeutically valuable substances.

The dosage can vary in wide limits and will, of course, be fitted to theindividual requirements in each particular case. In general, in the caseof oral administration a daily dosage of about 0.1 mg to 20 mg per kgbody weight, preferably about 0.5 mg to 4 mg per kg body weight (e.g.about 300 mg per person), divided into preferably 1-3 individual doses,which can consist, for example, of the same amounts, should beappropriate. It will, however, be clear that the upper limit givenherein can be exceeded when this is shown to be indicated.

In accordance with the invention, the compounds of formula (I) or theirpharmaceutically acceptable salts and esters can be used for thetreatment or prophylaxis of aldosterone mediated diseases.

The compounds of formula (I) or their pharmaceutically acceptable saltsand esters herein are inhibitors of CYP11B2. The compounds of formula(I) or their pharmaceutically acceptable salts and esters herein displayalso variable inhibition of CYP11B1 but present an improved selectivitytowards CYP11B2 versus CYP11B1. Such compounds may be used for treatmentor prophylaxis of conditions displaying excessive cortisolproduction/levels or both excessive cortisol and aldosterone levels (forex. Cushing syndrome, burn trauma patients, depression, post-traumaticstress disorders, chronic stress, corticotrophic adenomas, MorbusCushing).

In accordance with the invention, the compounds of formula (I) or theirpharmaceutically acceptable salts and esters can be used for thetreatment or prophylaxis of cardiovascular conditions (includinghypertension and heart failure), vascular conditions, endothelialdysfunction, baroreceptor dysfunction, renal conditions, liverconditions, fibrotic diseases, inflammatory conditions, retinopathy,neuropathy (such as peripheral neuropathy), pain, insulinopathy, edema,edematous conditions, depression and the like.

Cardiovascular conditions include congestive heart failure, coronaryheart disease, arrhythmia, arterial fibrillation, cardiac lesions,decreased ejection fraction, diastolic and systolic heart dysfunction,fibrinoid necrosis of coronary arteries, cardiac fibrosis, hypertrophiccardiomyopathy, impaired arterial compliance, impaired diastolicfilling, ischemia, left ventricular hypertrophy, myocardial and vascularfibrosis, myocardial infarction, myocardial necrotic lesions, cardiacarrhythmias, prevention of sudden cardiac death, restenosis, stroke,vascular damage.

Renal conditions include acute and chronic renal failure, nephropathy,end-stage renal disease, diabetic nephropathy, decreased creatinineclearance, decreased glomerular filtration rate, expansion ofreticulated mesangial matrix with or without significanthypercellularity, focal thrombosis of glomerular capillaries, globalfibrinoid necrosis, glomerulosclerosis, ischemic lesions, malignantnephrosclerosis (such as ischemic retraction, microalbuminuria,proteinuria, reduced renal blood flow, renal arteriopathy, swelling andproliferation of intracapillary (endothelial and mesangial) and/orextracapillary cells (crescents).

Renal conditions also include glomerulonephritis (such as diffuseproliferative, focal proliferative, mesangial proliferative,membranoproliferative, minimal change membranous glomerulonephritis),lupus nephritis, non-immune basement membrane abnormalities (such asAlport syndrome), renal fibrosis and glomerulosclerosis (such as nodularor global and focal segmental glomerulosclerosis).

Liver conditions include, but are not limited to, liver steatosis,nonalcoholic steatohepatitis, liver cirrhosis, liver ascites, hepaticcongestion and the like.

Vascular conditions include, but are not limited to, thrombotic vasculardisease (such as mural fibrinoid necrosis, extravasation andfragmentation of red blood cells, and luminal and/or mural thrombosis),proliferative arteriopathy (such as swollen myointimal cells surroundedby mucinous extracellular matrix and nodular thickening),atherosclerosis, decreased vascular compliance (such as stiffness,reduced ventricular compliance and reduced vascular compliance),endothelial dysfunction, and the like.

Inflammatory conditions include, but are not limited to, arthritis (forexample, osteoarthritis), inflammatory airways diseases (for example,chronic obstructive pulmonary disease (COPD)), and the like.

Pain includes, but is not limited to, acute pain, chronic pain (forexample, arthralgia), and the like.

Edema includes, but is not limited to, peripheral tissue edema, hepaticcongestion, liver ascites, splenic congestion, respiratory or lungcongestion, and the like.

Insulinopathies include, but are not limited to, insulin resistance,Type I diabetes mellitus, Type II diabetes mellitus, glucosesensitivity, pre-diabetic state, pre-diabetes, syndrome X, and the like.

Fibrotic diseases include, but are not limited to myocardial andintrarenal fibrosis, renal interstitial fibrosis and liver fibrosis.

Furthermore, the compounds of formula (I) or their pharmaceuticallyacceptable salts and esters as described herein can also be used for thetreatment or prophylaxis of cardiovascular condition selected from thegroup consisting of hypertension, heart failure (particularly heartfailure post myocardial infarction), left ventricular hypertrophy, andstroke.

In another embodiment, the cardiovascular condition is hypertension.

In particular embodiment, the cardiovascular condition istreatment-resistant hypertension.

In another embodiment, the cardiovascular condition is heart failure.

In another embodiment, the cardiovascular condition is left ventricularhypertrophy.

In another embodiment, the cardiovascular condition is congestive heartfailure, more particularly in patients with preserved left ventricularejection fraction.

In another embodiment, the cardiovascular condition is stroke.

In another embodiment, the compounds of formula (I) or theirpharmaceutically acceptable salts and esters can be used for thetreatment or prophylaxis renal condition.

In another embodiment, the renal condition is nephropathy.

In another embodiment, the renal condition is auto-immuneglomerulonephritis.

In another embodiment, the chronic kidney disease is diabeticnephropathy.

In another embodiment, the fibrotic disease is kidney or heart fibrosis.

In another embodiment, the compounds of formula (I) or theirpharmaceutically acceptable salts and esters can be used for thetreatment or prophylaxis Type II diabetes mellitus.

In another embodiment, the compounds of formula (I) or theirpharmaceutically acceptable salts and esters can be used for thetreatment or prophylaxis Type I diabetes mellitus.

In another embodiment, the compounds of formula (I) or theirpharmaceutically acceptable salts and esters can be used for thetreatment or prophylaxis of diabetic retinopathy.

The invention is illustrated hereinafter by Examples, which have nolimiting character.

In case the preparative examples are obtained as a mixture ofenantiomers, the pure enantiomers can be separated by methods describedherein or by methods known to the persons skilled in the art, such ase.g. chiral chromatography or crystallization.

EXAMPLES

All examples and intermediates were prepared under argon atmosphere ifnot specified otherwise.

Pyrazoles carrying a hydrogen substituent at any of the two nitrogenatoms and not symmetrical substituents at the 3 carbon atoms alwaysexist in two tautomeric forms.

Formulas and names describe any of the two forms.

Intermediate A-31-Methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydroquinolin-2-one

[A] 6-Bromo-1-methyl-3,4-dihydroquinolin-2-one

To a solution of 6-bromo-3,4-dihydro-1H-quinolin-2-one (5 g, 22.1 mmol)in DMF (100 mL) cooled to 0° C. was added potassium tert-butoxide (4.96g, 44.2 mmol) portion wise and the reaction mixture was stirred at 0° C.for 15 min. Then, methyl iodide (4.08 g, 28.8 mmol) was added and thereaction mixture allowed to warm up to room temperature and stirring wascontinued overnight. More methyl iodide (1.25 g, 8.86 mmol) was addedand the reaction mixture was heated to 40° C. until completion of thereaction. The mixture was diluted with EtOAc, poured into 100 mL of 1NHCl and the aqueous phase was extracted with EtOAc (2×200 mL). Thecombined organics were washed with brine, dried over anhy. Na₂SO₄,filtered and evaporated to dryness. The residue was purified by silicagel flash chromatography eluting with a 0 to 30% EtOAc-heptane gradientto give the title compound (4.23 g, 80%) as an off white solid. MS:240.0, 242.1 (M+H⁺).

[B]1-Methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydroquinolin-2-one

A flask was charged with 6-bromo-1-methyl-3,4-dihydroquinolin-2-one (3g, 12.5 mmol),4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (3.81 g,15.0 mmol), potassium acetate (3.68 g, 37.5 mmol) and dioxane (48 mL).The mixture was purged with Ar, thendichloro[1,1′-bis(diphenylphosphino)-ferrocene]palladium(II)dichloromethane complex (1:1) [PdCl₂(DPPF) dichloromethane adduct] (457mg, 0.560 mmol) was added and the resulting mixture was heated to 80° C.overnight. The reaction mixture was diluted with EtOAc, filtered throughCelite and washed with EtOAc (2×150 mL). The resulting filtrate waswashed with brine, dried over anhy. Na₂SO₄, filtered and evaporated todryness. The residue was purified by silica gel flash chromatographyeluting with a 0 to 40% EtOAc-heptane gradient to give the titlecompound (2.63 g, 73%) as an off white solid. MS: 288.0 (M+H⁺).

Intermediate A-47-Fluoro-1-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydroquinolin-2-one

[A] 3-Chloro-N-(3-fluoro-phenyl)-propionamide

To a solution of 3-fluoroaniline (10 mL, 104.02 mmol) in DCM (100 mL)was added pyridine (21 mL, 260.2 mmol) and 3-chloropropionyl chloride(12 mL, 124.4 mmol). The reaction mixture was stirred for 3 h at roomtemperature until all starting materials had disappeared as shown byLC-MS analysis. The reaction mixture was then diluted with H₂O andextracted with EtOAc. The organic layer was dried over anhy. Na₂SO₄ andconcentrated in vacuo to afford the title compound as a solid. It wasused in the next step without further purification.

[B] 7-Fluoro-3,4-dihydro-1H-quinolin-2-one

A flame-dried 50-mL flask equipped with a magnetic stirring bar wascharged with 3-chloro-N-(3-fluoro-phenyl)-propionamide (10 g, 49.6 mmol)and AlCl₃ (23.1 g, 173.6 mmol). On a pre-heated oil bath, the flask washeated to 120˜125° C. for 2 h until LC-MS indicated the reaction wascomplete. After cooling to room temperature, the mixture was treatedslowly with ice-water. After extraction with EtOAc, combined organicswere washed with water and brine in sequence. The organic layer wasdried over anhy. Na₂SO₄, filtered and concentrated in vacuo to afford awhite solid (7.63 g, 93.2%).

[C] 7-Fluoro-1-methyl-3,4-dihydro-1H-quinolin-2-one

To an ice cold solution of 7-fluoro-3,4-dihydro-1H-quinolin-2-one (16.5g, 0.1 mol) in DMF (200 mL) was added potassium tert-butoxide (22.4 g,0.2 mol) in 2 portions. The reaction mixture was stirred at 0° C. for 30min before methyl iodide (25.4 g, 0.18 mol) was added. After theaddition, the reaction mixture was allowed to warm up to roomtemperature slowly and stirred at room temperature overnight. It wasthen diluted with EtOAc (500 mL) and poured into 200 mL of 1 N aq. HCl.After extraction with EtOAc (3×200 mL), the combined organics werewashed with brine, dried over anhy. Na₂SO₄, filtered and concentrated invacuo to give the crude title compound as oil (16.0 g, 89%). It was usedin the next step without further purification.

[D] 6-Bromo-7-fluoro-1-methyl-3,4-dihydro-1H-quinolin-2-one

A mixture of 7-fluoro-1-methyl-3,4-dihydroquinolin-2-one (2.56 g, 0.014mol) and NBS (3.0 g, 0.017 mol) in DMF (30 mL) was stirred for 12 h at25° C. The reaction solution was diluted with H₂O (80 mL), and extractedwith EtOAc (3×100 mL). The combined organics were washed by brine (3×100mL), dried over anhy. Na₂SO₄ and concentrated in vacuo to give the titlecompound (1.5 g, 42%) as white foam. MS: 258.0, 259.9 (M+H⁺).

[E]7-Fluoro-1-methyl-6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,4-dihydro-1H-quinolin-2-one

In analogy to the procedure described for the preparation ofintermediates A-3 [B],6-bromo-7-fluoro-1-methyl-3,4-dihydro-1H-quinolin-2-one was reacted with4,4,4′,4′,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) in presence ofpotassium acetate and PdCl₂(DPPF)—CH₂Cl₂ to give the title compound as awhite solid. MS: 306.1 (M+H⁺).

Intermediate A-58-Chloro-1-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydroquinolin-2-one

[A] N-(4-Bromo-2-chloro-phenyl)-3-chloro-propionamide

To a solution of 4-bromo-2-chloro-phenylamine (32 g, 0.15 mol) andpyridine (13.45 g, 0.17 mol) in DCM (200 mL) was added 3-chloropropionylchloride (21.65 g, 0.17 mol) dropwise at 15° C. After stirring at roomtemperature for 1 hour, the mixture was washed with water and thenaqueous 2N HCl. The organic layer was dried over anhy. Na₂SO₄, filtered,and concentrated in vacuo to afford title compound (10.9 g, 90%) as awhite solid.

[B] 6-Bromo-8-chloro-3,4-dihydro-1H-quinolin-2-one

A flame-dried 500-mL flask equipped with a magnetic stirring bar wascharged with N-(4-bromo-2-chloro-phenyl)-3-chloro-propionamide (29.7 g,0.1 mol) and aluminium chloride (53.3 g, 0.4 mol). In a pre-heated oilbath, the flask was heated to 140° C. for 1 h. After cooling to roomtemperature, the mixture was treated slowly with ice-water and extractedwith EtOAc. The organic layer was washed with water and brine insequence, dried over anhy. Na₂SO₄, filtered, and concentrated in vacuo.The resulting residue was then purified by silica gel flashchromatography (30% ethyl acetate in hexane) to afford the titlecompound (7.0 g, 27%) as a white solid.

[C] 6-Bromo-8-chloro-1-methyl-3,4-dihydro-1H-quinolin-2-one

A solution of 6-bromo-8-chloro-3,4-dihydro-1H-quinolin-2-one (7.0 g,26.9 mmol) in DMF (100 mL) was treated with potassium tert-butoxide (6.0g, 53.8 mmol) at 0° C. portion wise. The resulting mixture was stirredat 0° C. for 30 min before methyl iodide (5.0 g, 35.0 mmol) was added.After stirring for 12 h, the reaction mixture was treated with water,extracted with EtOAc. The organic layer was washed with water and brinein sequence, and dried over anhy. Na₂SO₄. After removal of solvent underreduced pressure, the crude product (3.3 g, 45%) was obtained as a whitesolid.

[D]8-Chloro-1-methyl-6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,4-dihydro-1H-quinolin-2-one

A mixture of 6-bromo-8-chloro-1-methyl-3,4-dihydro-1H-quinolin-2-one(0.23 g, 0.84 mmol), bis(pinacolato)diboron (0.255 g, 1.01 mmol),1,1′-bis(diphenylphosphino)-ferrocene-dichloropalladium (II),dichloromethane complex (1:1) (30.7 mg, 0.04 mmol) and potassium acetate(0.247 g, 2.52 mmol) in dioxane (5 mL) was heated in a microwave at 80°C. overnight. After dilution with EtOAc, the organic layer was washedwith water, dried over anhy. Na₂SO₄ and concentrated in vacuo. Theresidue was then purified by silica gel flash chromatography (30% ethylacetate in hexane) to afford the title compound (0.17 g, 63%) as a whitesolid. MS: 322.2 (M+H⁺).

Intermediate A-65-Fluoro-1-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydroquinolin-2-one

[A] 2-(Bromomethyl)-1-fluoro-3-nitro-benzene

To a stirred solution of 1-fluoro-2-methyl-3-nitro-benzene (100 g, 0.64mol) and benzoyl peroxide (BPO) (15 g, 64 mmol) in CCl₄ (1500 mL) wasadded NBS (127 g, 0.73 mmol). The resulting reaction mixture was heatedto reflux for 12 h at 80° C. After TLC (PE:EA=20:1) indicated thecompletion of reaction, the reaction mixture was concentrated to removeCCl₄. The residue was diluted with DCM (500 mL), and washed with brine(2×300 mL). The organic layer was dried over anhy. Na₂SO₄ andconcentrated in vacuo to give a crude title product (160 g, 80%). It wasused in the next step without further purification.

[B] Diethyl 2-[(2-fluoro-6-nitro-phenyl)methyl]propanedioate

To a stirred solution of NaH (26 g, 0.65 mol) in DMF (500 mL) was addeddiethyl malonate (106 g, 0.66 mol) in 200 mL of DMF at 0° C. It wasstirred for 30 min at 0° C. before adding a solution of2-(bromomethyl)-1-fluoro-3-nitro-benzene (128 g, 0.55 mol) in DMF (600mL). The mixture was then allowed to warm up to room temperature andstirring was continued for 3 h before quenching by the addition of satd.aq. NH₄Cl (500 mL). The mixture was diluted with H₂O (2 L), and theaqueous layer was extracted with EtOAc (3×800 mL). The combined organicswere washed with brine (3×500 mL), dried over anhy. Na₂SO₄ andconcentrated in vacuo to give a crude title product (180 g, 70%). It wasused in the next step without further purification.

[C] Ethyl 5-fluoro-2-oxo-3,4-dihydro-1H-quinoline-3-carboxylate

To a stirred solution of diethyl2-[(2-fluoro-6-nitro-phenyl)methyl]propanedioate (126 g, 0.4 mol) andNH₄Cl (103 g, 2.4 mol) in EtOH/H₂O (5:1, 1200 mL) was added iron powder(67 g, 1.2 mol) at 80° C. portion wise. The resulting mixture wasrefluxed for 2 h at 80° C. After cooling to room temperature, thereaction mixture was filtered and the filtrate was concentrated in vacuoto give a crude title product (92 g, 50%). MS: 238.1 (M+H⁺). It was usedin the next step without further purification.

[D] 5-Fluoro-3,4-dihydro-1H-quinolin-2-one

A solution of ethyl5-fluoro-2-oxo-3,4-dihydro-1H-quinoline-3-carboxylate (46 g, 0.19 mol)in AcOH (300 mL) and HCl (150 mL) was heated to 90° C. for 1 h before itwas concentrated under reduced pressure. Saturated aqueous Na₂CO₃solution (500 mL) was carefully added to the residue, then it wasdiluted with additional H₂O (1 L), and extracted with EtOAc (3×300 mL).The combined organics were washed with brine (2×500 mL), dried overanhy. Na₂SO₄ and concentrated in vacuo to give a crude title product (28g, 89.3%). MS: 166.1 (M+H⁺). It was used in the next step withoutfurther purification.

[E] 5-Fluoro-1-methyl-3,4-dihydroquinolin-2-one

To a solution of NaH (8.1 g, 0.20 mol) in DMF (200 mL) was added5-fluoro-3,4-dihydro-1H-quinolin-2-one (28 g, 0.17 mol) in 100 mL of DMFat 0° C. The resulting reaction mixture was stirred at 0° C. for 10 minbefore methyl iodide (30 g, 0.21 mmol) was added. After the addition, itwas allowed to warm up to room temperature and stirred for 1 h. Thereaction was then quenched by the addition of satd. aq. NH₄Cl (200 mL),diluted with H₂O (1 L), and extracted with EtOAc (3×300 mL). Thecombined organics were washed with brine (3×500 mL), dried over anhy.Na₂SO₄ and concentrated in vacuo to give crude title compound (32 g,80%). MS: 180.1 (M+H⁺). It was used in the next step without furtherpurification.

[F] 6-Bromo-5-fluoro-1-methyl-3,4-dihydroquinolin-2-one

To a solution of 5-fluoro-1-methyl-3,4-dihydroquinolin-2-one (25.6 g,0.14 mol) in DMF (300 mL) was added NBS (30 g, 0.17 mol) and theresulting reaction mixture was stirred at room temperature for 12 h. Itwas diluted with H₂O (800 mL), and the aqueous layer was extracted withEtOAc (3×200 mL). The combined organics were washed with brine (3×300mL), dried over anhy. Na₂SO₄ and concentrated in vacuo to give crudetitle compound (15 g, 42%). MS: 256.1 and 258.1 (M+H⁺).

[G]5-Fluoro-1-methyl-6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,4-dihydro-1H-quinolin-2-one

A flask was charged with6-bromo-5-fluoro-1-methyl-3,4-dihydroquinolin-2-one (14.5 g, 56 mmol),4,4,4′,4′,5,5,5,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (28 g, 113mmol), potassium acetate (11 g, 113 mmol) and DMSO (300 mL). The mixturewas purged with Ar, thendichloro[1,1′-bis(diphenylphosphino)-ferrocene]palladium(II)dichloromethane complex (1:1) [PdCl₂(DPPF)—CH₂Cl₂ adduct] (2.2 g, 2.8mmol) was added and the resulting mixture was heated to 80° C. for 3 h.The reaction mixture was filtered and the filtrate was diluted withsatd. aq. NH₄Cl (200 mL) and H₂O (1 L). The aqueous layer was extractedwith EtOAc (3×200 mL) and the combined organics were washed with brine(2×200 mL), dried over anhy. Na₂SO₄, filtered and evaporated to dryness.The residue was purified by silica gel flash chromatography eluting witha 0 to 20% EtOAc-heptane gradient to give the desired title compound(7.9 g, 46.5%) as an off white solid. MS: 306.0 (M+H⁺).

Intermediate A-75-Chloro-1-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydroquinolin-2-one

[A] 2-(Bromomethyl)-1-chloro-3-nitro-benzene

A solution of 1-chloro-2-methyl-3-nitro-benzene (25.0 g, 145.7 mmol),N-bromosuccinimide (30.0 g, 16.8 mmol) and benzoyl peroxide (2.5 g, 10.4mmol) in carbon tetrachloride (300 mL) was heated to 100° C. for 10 h.After TLC indicated the reaction was completed, the reaction mixture wasfiltered and the filtrate was concentrated in vacuo to give crudeproduct as yellow oil (40.0 g, 100%). MS: 250.1 (M+H)⁺. It was used inthe next step without further purification.

[B] Diethyl 2-[(2-chloro-6-nitro-phenyl)methyl]propanedioate

A solution of 2-(bromomethyl)-1-chloro-3-nitro-benzene (50.0 g, 199.6mmol), diethyl malonate (40.0 g, 260.0 mmol) and cesium carbonate (97.5g, 300.0 mmol) in DMF (550 mL) was stirred at 0° C. for 10 min and thenat room temperature for additional 2 h. The reaction was quenched by aq.1 N HCl (300 mL), and the aqueous layer was extracted with diethyl ether(3×500 mL). After filtration, the organic layer was dried over anhy.Na₂SO₄, and concentrated in vacuo to give crude compound as yellow oil(68.0 g, 100%). MS: 330.1 (M+H)⁺. It was used in the next step withoutfurther purification.

[C] 5-Chloro-3,4-dihydro-1H-quinolin-2-one

A solution of diethyl 2-[(2-chloro-6-nitro-phenyl)methyl] propanedioate(20 g, 61.9 mmol), stannous chloride dehydrate (100 g, 443.0 mmol) in 6Naq. HCl (400 mL) was heated to 130° C. for 5 h. The reaction mixturewas extracted with DCM (4×200 mL), and washed with brine. The organiclayer was dried over anhy. Na₂SO₄, filtered, and concentrated in vacuoto afford crude title compound as a yellow solid (18.0 g, 80%). MS:181.9 (M+H)⁺.

[D] 5-Chloro-1-methyl-3,4-dihydroquinolin-2-one

To a solution of 5-chloro-3,4-dihydro-1H-quinolin-2-one (16.0 g, 88.4mmol), t-BuONa (16.0 g, 166.7 mmol) in THF (200 mL) was added methyliodide (16.0 g, 140.4 mmol) drop wise at 0° C. After the addition, thereaction mixture was slowly warmed up to room temperature and stirredovernight. It was then quenched with satd. aq. NaCl solution, extractedwith diethyl ether (200 mL×3), dried over anhy. Na₂SO₄, and concentratedin vacuo. The residue was purified by silica gel flash chromatography toafford the desired title compound as a pale yellow solid (16.0 g, 82%).MS: 196.1 (M+H)⁺.

[E] 6-Bromo-5-chloro-1-methyl-3,4-dihydroquinolin-2-one

To a solution of 5-chloro-1-methyl-3,4-dihydroquinolin-2-one (15.2 g,77.6 mmol) in DMF (250 mL) was added bromosuccinimide (15.2 g, 85.4mmol) portion wise at 0° C. After the addition, the reaction mixture wasallowed to warm up to room temperature and stirred overnight. Thereaction was diluted with water (500 mL), extracted with diethyl ether(4×200 mL), dried over anhy. Na₂SO₄, and concentrated in vacuo. Theresidue was then purified by silica gel flash chromatography to affordthe desired title compound as a brown solid (16.0 g, 75%). MS: 274.9(M+H)⁺.

[F]5-Chloro-1-methyl-6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,4-dihydro-1H-quinolin-2-one

A stirred solution of6-bromo-5-chloro-1-methyl-3,4-dihydroquinolin-2-one (5.0 g, 18.2 mmol),bis(pinacolato)diboron (7.5 g, 29.5 mmol), PdCl₂(DPPF)—CH₂Cl₂ (1.0 g,1.23 mmol), KOAc (6.0 g, 61.2 mmol) in degassed dioxane (100 mL) andDMSO (10 mL) was heated to 90° C. overnight. After cooling to roomtemperature, the reaction mixture was filtered and the filtrate wasdiluted with diethyl ether, washed with brine, dried over anhy. Na₂SO₄,and concentrated in vacuo to give a crude product, which was thenpurified by silica gel flash chromatography to afford desired titlecompound as a white solid (2.8 g, 47%). MS: 322.2 (M+H)⁺.

Intermediate A-84-[[3-Iodo-1-[(4-methoxyphenyl)methyl]pyrazol-4-yl]methyl]piperidine

[A] 4-Iodo-1-[(4-methoxyphenyl)methyl]pyrazole

To a solution of 4-iodo-1H-pyrazole (5.82 g, 30 mmol) in DMF (50 mL) wasadded NaH (1.8 g, 45 mmol) portion wise at 0° C. It was stirred at 0° C.for 30 min before the addition of PMBCl (5.15 g, 33 mmol) drop wise. Theresulting mixture was warmed up to room temperature slowly and stirredovernight. It was poured into satd. aq. NH₄Cl (300 mL), and the aqueouslayer was extracted with EtOAc (3×200 mL). The combined organics werewashed with brine (200 mL), dried over anhy. Na₂SO₄ and concentrated invacuo. The residue was purified by silica gel flash chromatography (0 to40% EtOAc in petroleum ether) to give desired title compound as a whitesolid (7.5 g, 79.6%). MS: 315.1 (M+H)⁺.

[B] (rac)-tert-Butyl4-[hydroxy-[1-[(4-methoxyphenyl)methyl]pyrazol-4-yl]methyl]piperidine-1-carboxylate

To a solution of 4-iodo-1-[(4-methoxyphenyl)methyl]pyrazole (6.28 g, 20mmol) in THF (80 mL) was added n-BuLi (9.6 mL, 24 mmol) drop wise at−78° C. After stirring for 15 min, a solution of tert-butyl4-formylpiperidine-1-carboxylate (5.11 g, 24 mmol) in THF (20 mL) wasadded drop wise while keeping the temperature below −65° C. Theresulting mixture was stirred at −78° C. for 1 h before warming up toroom temperature. After TLC (PE:EA=1:1) indicated the completion of thereaction, the mixture was poured into satd. aq. NH₄Cl (100 mL) and theaqueous layer was extracted with EtOAc (3×100 mL). The combined organicswere washed with brine (100 mL), dried over anhy. Na₂SO₄ andconcentrated in vacuo. The residue was purified by silica gel flashchromatography (0 to 80% EtOAc in petroleum ether) to give desired titlecompound as a yellow solid (4 g, 50%). MS: 402.1 [M+H⁺].

[C] tert-Butyl4-[[1-[(4-methoxyphenyl)methyl]pyrazol-4-yl]methylene]piperidine-1-carboxylate

To a solution of (rac)-tert-butyl4-[hydroxy-[1-[(4-methoxyphenyl)methyl]pyrazol-4-yl]methyl]piperidine-1-carboxylate(4.01 g, 10 mmol) in DCM (50 mL) cooled to 0° C. was added CBr₄ (3.98 g,12 mmol) and Ph₃P (3.14 g, 12 mmol) slowly and the mixture was stirredat 0° C. for 4 h. After evaporation of the solvent, the residue waspurified by silica gel flash chromatography (0 to 40% EtOAc in petroleumether) to give desired title compound as colorless oil (1.5 g, 39%). MS:383.9 [M+H⁺].

[D] tert-Butyl4-[[1-[(4-methoxyphenyl)methyl]pyrazol-4-yl]methyl]piperidine-1-carboxylate

A solution of tert-butyl4-[[1-[(4-methoxyphenyl)methyl]pyrazol-4-yl]methylene]piperidine-1-carboxylate(1.5 g, 3.9 mmol) and Pd/C (200 mg) in EtOAc (50 mL) was stirred at roomtemperature under H₂ (15 psi). After 15 min, TLC (EA:PE=1:1) showed thecompletion of the reaction and the reaction mixture was concentrated invacuo to give desired crude product as colorless oil (800 mg, 53%). MS:385.8 [M+H⁺]. It was used in the next step without further purification.

[E] 4-[[3-Iodo-1-[(4-methoxyphenyl)methyl]pyrazol-4-yl]methyl]piperidine

To a solution of tert-butyl4-[[1-[(4-methoxyphenyl)methyl]pyrazol-4-yl]methyl]-piperidine-1-carboxylate(770 mg, 0.2 mmol) in HOAc (8 mL) was added a solution of ICl (390 mg,2.4 mmol) in HOAc (2 mL) slowly followed by the addition of 1.5 mL ofwater (1.5 mL). The resulting mixture was heated to 85° C. for 18 h.After evaporation of the solvent, a crude product was obtained as yellowoil (900 mg). MS: 411.7 [M+H⁺]. It was used in the next step withoutfurther purification.

Intermediate A-9 tert-Butyl4-[(3-iodo-1H-pyrazol-4-yl)methyl]piperidine-1-carboxylate

[A] 4-Iodo-1-tetrahydropyran-2-yl-pyrazole

A stirred solution of 4-iodo pyrazole (30.0 g, 155.4 mmol), DHP (80.0 g,952.4 mmol), TFA (1.3 g, 0.93 mmol) in toluene (400 mL) was heated at80° C. for 1 h. After cooling to the room temperature, it was quenchedwith satd. aq. Na₂CO₃ solution. Then, the solvent was removed underreduced pressure to give a crude product, which was purified by silicagel flash chromatography to afford the desired title compound (39 g,90%) as colorless oil. MS: 279.4 [M+H⁺].

[B] tert-Butyl4-[hydroxy-(1-tetrahydropyran-2-ylpyrazol-4-yl)methyl]piperidine-1-carboxylate

To a solution of 4-iodo-1-tetrahydropyran-2-yl-pyrazole (11.2 g, 40mmol) in THF (80 mL) was added iPrMgCl (1.3 M in THF, 40 mmol) drop wiseat 0° C. After the addition, the reaction mixture was warmed up to roomtemperature and stirred for 1 h before tert-butyl4-formylpiperidine-1-carboxylate (8.5 g, 40 mmol) in THF (20 mL) wasadded drop wise at room temperature. The resulting mixture was stirredat room temperature overnight and then poured into a satd. aq. NH₄Clsolution. The aqueous layer was extracted with EtOAc. The combinedorganic layers were washed with brine, dried over anhy. Na₂SO₄ andconcentrated in vacuo. The residue was then purified by silica gel flashchromatography to give desired title compound (14.0 g, 95%) as a yellowsolid. MS: 366.1 [M+H⁺].

[C] 4-(1H-Pyrazol-4-ylmethyl)piperidine

To a solution of tert-butyl4-[hydroxy-(1-tetrahydropyran-2-ylpyrazol-4-yl)methyl]piperidine-1-carboxylate(9.0 g, 24.5 mmol) in Et₃SiH (200 mL) was added TFA (100 mL) drop wiseat 0° C. After the addition, the mixture was slowly warmed up to roomtemperature and stirred at room temperature for 48 h. The solvent wasevaporated to dryness to afford a crude product (10.0 g, 100%) ascolorless oil. It was used in the next step without furtherpurification. MS: 166.1 [M+H⁺].

[D] tert-Butyl4-[(1-tert-butoxycarbonylpyrazol-4-yl)methyl]piperidine-1-carboxylate

To a solution of 4-(1H-pyrazol-4-ylmethyl)piperidine (10.0 g crude, 24.5mmol), TEA (30.0 g, 297.0 mmol) in DCM (150 mL) was added di-tert-butyldicarbonate (20.0 g, 92.5 mmol) portion wise at 0° C. The mixture wasslowly warmed up to room temperature and stirred for 2 h. It was thenwashed with satd. aq. NaHCO₃ solution, and the organic layer was driedover anhy. Na₂SO₄. After filtration, the filtrate was concentrated undervacuum to give a crude product, which was purified by silica gel flashchromatography to afford desired title compound (2.0 g, 22%) ascolorless oil. MS: 366.1 [M+H⁺].

[E] tert-Butyl 4-(1H-pyrazol-4-ylmethyl)piperidine-1-carboxylate

A solution of tert-butyl4-[(1-tert-butoxycarbonylpyrazol-4-yl)methyl]piperidine-1-carboxylate(2.0 g, 5.4 mmol), LiOH hydrate (2.0 g, 47.6 mmol) in EtOH (30 mL) andwater (30 mL) was stirred at room temperature for 2 h. The reactionmixture was then extracted with DCM, and the organic layer was driedover anhy. Na₂SO₄ and filtered. The filtrate was concentrated in vacuoto give a crude product, which was purified by silica gel flashchromatography to afford desired title compound (950 mg, 65%) ascolorless oil. MS: 266.1 [M+H⁺].

[F] tert-Butyl4-[(3-iodo-1H-pyrazol-4-yl)methyl]piperidine-1-carboxylate

To a solution of tert-butyl4-(1H-pyrazol-4-ylmethyl)piperidine-1-carboxylate (900 mg, 3.4 mmol) inDMF (20 mL) was added NIS (2.5 g, 11.1 mmol) portion wise at roomtemperature and stirred at room temperature overnight. LC-MS indicatedabout 40% desired and 60% di-iodo by product. The solvent was evaporatedand the residue was purified by silica gel flash chromatography toafford desired title compound (470 mg, 33%) as a yellow gum. MS: 392.3[M+H⁺].

Example 166-[4-[(1-Acetyl-4-piperidyl)methyl]-1H-pyrazol-3-yl]-1-methyl-3,4-dihydroquinolin-2-one

[A] tert-Butyl4-[[3-(1-methyl-2-oxo-3,4-dihydroquinolin-6-yl)-1H-pyrazol-4-yl]methyl]piperidine-1-carboxylate

In a microwave vial, tert-butyl4-[(3-iodo-1H-pyrazol-4-yl)methyl]piperidine-1-carboxylate (intermediateA-9) (700 mg, 1.8 mmol),1-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydroquinolin-2-one(intermediate A-3) (576 mg, 2.0 mmol), PdCl₂(DPPF)—CH₂Cl₂ (100 mg, 0.12mmol) and Na₂CO₃ (318 mg, 3.0 mmol) in dioxane (6 mL) and water (6 mL)were heated to 110° C. under microwave irradiation for 1 h. Aftercooling to room temperature, the reaction mixture was extracted withDCM. The organic layer was washed with brine, dried over anhy. Na₂SO₄,and concentrated in vacuo to give a crude product, which was purified bysilica gel flash chromatography to afford the desired title compound asa yellow solid (700 mg, 91%). MS: 425.3 [M+H⁺].

[B]1-Methyl-6-[4-(4-piperidylmethyl)-1H-pyrazol-3-yl]-3,4-dihydroquinolin-2-one

To a solution of tert-butyl4-[[3-(1-methyl-2-oxo-3,4-dihydroquinolin-6-yl)-1H-pyrazol-4-yl]methyl]piperidine-1-carboxylate(700 mg, 1.65 mmol) in MeOH (15 mL) was added acetyl chloride (5 mL)drop wise at 0° C. The resulting reaction mixture was stirred at roomtemperature overnight. After evaporation of the solvent, the crude titlecompound was obtained as a yellow solid (700 mg, 100%). MS: 325.3[M+H⁺]. It was used in the next step without further purification.

[C]6-[4-[(1-Acetylpiperidin-4-yl)methyl]-1H-pyrazol-3-yl]-1-methyl-3,4-dihydroquinolin-2-one

To a solution of1-methyl-6-[4-(4-piperidylmethyl)-1H-pyrazol-3-yl]-3,4-dihydroquinolin-2-one(60 mg, 0.17 mmol), Et₃N (500 mg, 5 mmol) in DCM (5 mL) was added acetylchloride (13 mg, 0.17 mmol) drop wise at 0° C. The resulting reactionmixture was allowed to stir at room temperature for 2 h before thesolvent was evaporated to dryness. The residue was subjected toprep-HPLC separation to give desired title compound (8 mg, 12.9%) as awhite solid. MS: 367.2 [M+H⁺].

Example 171-Methyl-6-[4-[[1-(1-methylpyrazole-4-carbonyl)-4-piperidyl]methyl]-1H-pyrazol-3-yl]-3,4-dihydroquinolin-2-one

A solution of1-methyl-6-[4-(4-piperidylmethyl)-1H-pyrazol-3-yl]-3,4-dihydroquinolin-2-one(Example 16[B], 60 mg, 0.17 mmol), 1-methylpyrazole-4-carboxylic acid(30 mg, 0.24 mmol), Et₃N (200 mg, 2.0 mmol) and HATU (86 mg, 0.20 mmol)in DCM (5 mL) was stirred at room temperature for 2 h. The solvent wasthen removed under reduced pressure and the residue was re-dissolved in2 N aq. NaOH (5 mL) and extracted with DCM. The organic layer was washedwith brine, dried over anhy. Na₂SO₄, and concentrated in vacuo to give acrude product, which was purified by silica gel falsh chromatography toafford the desired title compound (9 mg, 12.3%) as a white solid. MS:433.1 [M+H⁺].

Example 186-[4-[(1-Ethylsulfonyl-4-piperidyl)methyl]-1H-pyrazol-3-yl]-1-methyl-3,4-dihydroquinolin-2-one

To a stirred solution of1-methyl-6-[4-(4-piperidylmethyl)-1H-pyrazol-3-yl]-3,4-dihydroquinolin-2-one(Example 16[B], 60 mg, 0.17 mmol), Et₃N (500 mg, 5 mmol) in DCM (5 mL)was added ethanesulfonyl chloride (22 mg, 0.17 mmol) drop wise at 0° C.The resulting reaction mixture was allowed to stir at room temperaturefor 2 h before the solvent was evaporated to dryness. The residue wassubjected to prep-HPLC separation to give desired title compound (6 mg,8.5%) as a white solid. MS: 417.3 [M+H⁺].

Example 196-[4-[(1-Acetylpiperidin-4-yl)methyl]-1H-pyrazol-3-yl]-7-fluoro-1-methyl-3,4-dihydroquinolin-2-one

[A]1-[4-[[3-Iodo-1-[(4-methoxyphenyl)methyl]pyrazol-4-yl]methyl]-1-piperidyl]ethanone

To a stirred solution of4-[[3-iodo-1-[(4-methoxyphenyl)methyl]pyrazol-4-yl]methyl]-piperidine(intermediate A-8, 800 mg, 2 mmol) and Et₃N (0.50 mL) in DCM (10 mL) wasadded acetyl chloride (0.2 mL, 3 mmol) at 0° C. and stirring continuedat 0° C. for 1 h. The resulting mixture was extracted with EtOAc (2×100mL) and the combined organics were washed with brine, dried over anhy.Na₂SO₄, filtered and concentrated in vacuo to afford a crude product. Itwas then purified by silica gel flash chromatography eluting with a 0 to50% EtOAc-heptane gradient to give the desired title compound (630 mg,67.5%) as yellow oil. MS: 454.1 (M+H⁺).

[B]6-[4-[(1-Acetyl-4-piperidyl)methyl]-1-[(4-methoxyphenyl)methyl]pyrazol-3-yl]-7-fluoro-1-methyl-3,4-dihydroquinolin-2-one

To a stirred solution of1-[4-[[3-iodo-1-[(4-methoxyphenyl)methyl]pyrazol-4-yl]methyl]-1-piperidyl]ethanone(200 mg, 0.43 mmol) in dioxane/H₂O (6:1, 7 mL) was added7-fluoro-1-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydroquinolin-2-one(intermediate A-4, 144 mg, 0.473 mmol), Cs₂CO₃ (280 mg, 0.856 mmol) andPdCl₂(DPPF)—CH₂Cl₂ (20 mg). The mixture solution was stirred at 100° C.for 3 h, then poured into satd. aq. NaCl solution (20 mL) and extractedwith EtOAc (2×60 mL). The combined organics were washed with brine (30mL), dried over anhy. Na₂SO₄ and concentrated in vacuo to give a crudeproduct, which was purified by silica gel flash chromatography elutingwith a 0 to 30% methanol-DCM gradient to afford the desired titlecompound as yellow oil (130 mg, 58.5%). MS: 505.1 (M+H⁺).

[C]6-[4-[(1-Acetylpiperidin-4-yl)methyl]-1H-pyrazol-3-yl]-7-fluoro-1-methyl-3,4-dihydroquinolin-2-one

To a stirred solution of6-[4-[(1-acetyl-4-piperidyl)methyl]-1-[(4-methoxyphenyl)-methyl]pyrazol-3-yl]-7-fluoro-1-methyl-3,4-dihydroquinolin-2-one(110 mg) in MeOH (20 mL) was added Pd(OH)₂ (50 mg) and two drops of AcOHat room temperature. The reaction solution was stirred at 40° C. for 24h under H₂ (50 psi). Then, the solution was filtered and the filtratewas concentrated under reduced pressure to give a crude product, whichwas purified by prep-HPLC to afford the desired title compound as whitefoam (26 mg, 31.3%). MS: 385.1 (M+H⁺).

Example 205-Fluoro-1-methyl-6-[4-[[1-(1-methylpyrazole-4-carbonyl)piperidin-4-yl]methyl]-1H-pyrazol-3-yl]-3,4-dihydroquinolin-2-one

[A] tert-Butyl4-[[3-iodo-1-[(4-methoxyphenyl)methyl]pyrazol-4-yl]methyl]piperidine-1-carboxylate

To a solution of4-[[3-iodo-1-[(4-methoxyphenyl)methyl]pyrazol-4-yl]methyl]piperidine(intermediate A-8, 2.46 g, 8.1 mmol), Et₃N (3.0 g, 30 mmol) in MeOH (50mL) was added di-tert-butyl dicarbonate (2.2 g, 10 mmol) portion wise at0° C. and stirring continued at room temperature overnight. After thesolvent was evaporated under reduced pressure, the residue was purifiedby silica gel flash chromatography to afford the title compound ascolorless oil (2.2 g, 52%). MS: 512.1 [M+H⁺].

[B] tert-Butyl4-[[3-(5-fluoro-1-methyl-2-oxo-3,4-dihydroquinolin-6-yl)-1-[(4-methoxyphenyl)methyl]pyrazol-4-yl]methyl]piperidine-1-carboxylate

A solution of tert-butyl4-[[3-iodo-1-[(4-methoxyphenyl)methyl]pyrazol-4-yl]methyl]-piperidine-1-carboxylate(1.10 g, 2.1 mmol),5-fluoro-1-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydroquinolin-2-one(460.0 mg, 1.70 mmol) (intermediate A-6), PdCl₂(DPPF) (100.0 mg, 0.14mmol) and cesium carbonate (1000 mg, 3.1 mmol) in degassed dioxane (8mL) and water (2 mL) was heated to 85° C. for 3 h. After cooling to roomtemperature, the solvent was evaporated under reduced pressure and theresidue was dried under vacuum to give a crude product, which waspurified by silica gel flash column chromatography to afford the desiredtitle compound as colorless oil (259 mg, 23%). MS: 563.3 [M+H⁺].

[C]5-Fluoro-6-[1-[(4-methoxyphenyl)methyl]-4-(4-piperidylmethyl)pyrazol-3-yl]-1-methyl-3,4-dihydroquinolin-2-one

To a solution of tert-butyl4-[[3-(5-fluoro-1-methyl-2-oxo-3,4-dihydroquinolin-6-yl)-1-[(4-methoxyphenyl)methyl]pyrazol-4-yl]methyl]piperidine-1-carboxylate(259 mg, 0.58 mmol) in methanol (5 mL) was added acetyl chloride (1.5mL) drop wise at 0° C. and the resulting mixture was stirred at roomtemperature for 1 h. The reaction mixture was concentrated in vacuo togive a crude title compound (261 mg, 100%). MS: 463.3 [M+H⁺]. It wasused in the next step without further purification.

[D] 5-Fluoro-6-[1-[(4-methoxyphenyl)l]-4-[[1-(1-methylpyrazole-4-carbonyl)-4-piperidyl]methyl]pyrazol-3-yl]-1-methyl-3,4-dihydroquinolin-2-one

A solution of5-fluoro-6-[1-[(4-methoxyphenyl)methyl]-4-(4-piperidylmethyl)pyrazol-3-yl]-1-methyl-3,4-dihydroquinolin-2-one(261 mg, 0.56 mmol), 1-methylpyrazole-4-carboxylic acid (113 mg, 0.9mmol), HATU (380 mg, 1.0 mmol), DIPEA (500 mg, 3.8 mmol) in DCM (5 mL)was stirred at room temperature for 4 h. After evaporation of solvent,the crude product was purified by silica gel flash chromatography toafford the desired title compound as colorless oil (265 mg, 82%). MS:571.4 [M+H⁺].

[E]5-Fluoro-1-methyl-6-[4-[[1-(1-methylpyrazole-4-carbonyl)piperidin-4-yl]methyl]-1H-pyrazol-3-yl]-3,4-dihydroquinolin-2-one

In a microwave vial,5-fluoro-6-[1-[(4-methoxyphenyl)methyl]-4-[[1-(1-methylpyrazole-4-carbonyl)-4-piperidyl]methyl]pyrazol-3-yl]-1-methyl-3,4-dihydroquinolin-2-one(265 mg, 0.46 mmol) in 3 mL of TFA was heated to 150° C. under microwaveirradiation for 10 min.

The solvent was evaporated under reduced pressure and the crude productwas purified by prep-HPLC to give the desired title compound as a whitesolid (25 mg, 12% yield). MS: 451.3 [M+H⁺].

Example 216-[4-[(1-Acetyl-4-piperidyl)methyl]-1H-pyrazol-3-yl]-5-fluoro-1-methyl-3,4-dihydroquinolin-2-one

[A]6-[4-[(1-Acetyl-4-piperidyl)methyl]-1-[(4-methoxyphenyl)methyl]pyrazol-3-yl]-5-fluoro-1-methyl-3,4-dihydroquinolin-2-one

To a solution of5-fluoro-6-[1-[(4-methoxyphenyl)methyl]-4-(4-piperidylmethyl)pyrazol-3-yl]-1-methyl-3,4-dihydroquinolin-2-one(intermediate 20[C], 261 mg, 0.56 mmol), Et₃N (282 mg, 2.8 mmol) in DCM(5 mL) was added acetyl chloride (70 mg, 0.9 mmol) drop wise at 0° C.The resulting mixture was stirred at room temperature for 1 h before itwas evaporated to dryness. The crude product was then purified by silicagel flash chromatography to give the desired title compound as a whitesolid (100 mg, 35%). MS: 505.4 [M+H⁺].

[B]6-[4-[(1-Acetyl-4-piperidyl)methyl]-1H-pyrazol-3-yl]-5-fluoro-1-methyl-3,4-dihydroquinolin-2-one

In analogy to the procedure described for the synthesis of Example20[E],6-[4-[(1-acetyl-4-piperidyl)methyl]-1-[(4-methoxyphenyl)methyl]pyrazol-3-yl]-5-fluoro-1-methyl-3,4-dihydroquinolin-2-one(100 mg, 0.19 mmol) was used to give, after prep-HPLC separation, thedesired title compound as a white solid (20 mg, 12%). MS: 385.2 [M+H⁺].

The following compounds listed in Table 2 were prepared in analogy tothe procedures described for the preparation of examples 16-21 usingappropriate starting materials.

TABLE 2 Name Example MS Example Aspect Reactants procedures (M + H⁺) 22

5-Fluoro-1- methyl-6- (4,4,5,5- tetramethyl-1,3,2- dioxaborolan-2-yl)-3,4- dihydroquinolin- 2-one (intermediate A- 6) and ethanesulfonylchloride 18 435.2 23

5-Fluoro-1- methyl-6- (4,4,5,5- tetramethyl-1,3,2- dioxaborolan-2-yl)-3,4- dihydroquinolin- 2-one (intermediate A- 6) and 2-methyl-pyrazole-3- carboxylic acid 17 451.3 24

5-Fluoro-1- methyl-6- (4,4,5,5- tetramethyl-1,3,2- dioxaborolan-2-yl)-3,4- dihydroquinolin- 2-one (intermediate A- 6) and 1-methyl-imidazole-2- carboxylic acid 17 451.3 25

5-Chloro-1- methyl 6- (4,4,5,5- tetramethyl-1,3,2- dioxaborolan-2-yl)-3,4- dihydroquinolin- 2-one (intermediate A- 7) and acetyl chloride16 401.2 26

1-Methyl-6- (4,4,5,5- tetramethyl-1,3,2- dioxaborolan-2- yl)-3,4-dihydroquinolin- 2-one (Intermediate A- 3) and 2-methyl- pyrazole-3-carboxylic acid 17 433.1 27

5-Chloro-1- methyl-6- (4,4,5,5- tetramethyl-1,3,2- dioxaborolan-2-yl)-3,4- dihydroquinolin- 2-one (intermediate A- 7) and 1-methyl-pyrazole-4- carboxylic acid 17 467.2 28

5-Chloro-1- methyl-6- (4,4,5,5- tetramethyl-1,3,2- dioxaborolan-2-yl)-3,4- dihydroquinolin- 2-one (intermediate A- 7) and 3-chloro-pyridine-2- carboxylic acid 17 498.1 29

5-Chloro-1- methyl-6- (4,4,5,5- tetramethyl-1,3,2- dioxaborolan-2-yl)-3,4- dihydroquinolin- 2-one (intermediate A- 7) and 2-methyl-pyrazole-3- carboxylic acid 20 467.1 30

5-Chloro-1- methyl-6- (4,4,5,5- tetramethyl-1,3,2- dioxaborolan-2-yl)-3,4- dihydroquinolin- 2-one (intermediate A- 7) and 3-chloro-pyridine-4- carboxylic acid 17 498.4 31

1-Methyl-6- (4,4,5,5- tetramethyl-1,3,2- dioxaborolan-2- yl)-3,4-dihydroquinolin- 2-one (intermediate A- 3) and 3-methyl- imidazole-4-carboxylic acid 17 433.3 32

1-Methyl-6- (4,4,5,5- tetramethyl-1,3,2- dioxaborolan-2- yl)-3,4-dihydroquinolin- 2-one (intermediate A- 3) and 1-methyl- imidazole-2-carboxylic acid 17 433.3 33

1-Methyl-6- (4,4,5,5- tetramethyl-1,3,2- dioxaborolan-2- yl)-3,4-dihydroquinolin- 2-one (intermediate A- 3) and 4-methyl- pyridine-3-carboxylic acid 17 444.1 34

1-Methyl-6- (4,4,5,5- tetramethyl-1,3,2- dioxaborolan-2- yl)-3,4-dihydroquinolin- 2-one (intermediate A- 3) and 3-chloro- pyridine-2-carboxylic acid 17 464.1

Example 35(rac)-6-[4-[1-(1-Acetylpiperidin-4-yl)ethyl]-1H-pyrazol-3-yl]-7-fluoro-1-methyl-3,4-dihydroquinolin-2-one

[A] (rac)-tert-Butyl4-[1-hydroxy-1-[1-[(4-methoxyphenyl)methyl]pyrazol-3-yl]ethyl]piperidine-1-carboxylate

To a solution of 4-iodo-1-[(4-methoxyphenyl)methyl]pyrazole(intermediate A-8[A], 12.6 g, mmol) in THF (80 mL) was addedisopropylmagnesium chloride (1.3 M, 30 mL, 40 mmol) at 0° C. Theresulting mixture was stirred at 0° C. for 1 h and allowed to warm up toroom temperature before tert-butyl 4-acetylpiperidine-1-carboxylate (9.1g, 40 mmol) was added and the resulting mixture was stirred at roomtemperature for additional 12 h. It was then poured into satd. aq. NaCl(50 mL) and extracted with EtOAc (3×150 mL). The combined organic layerswere washed with brine (200 mL), dried over anhy. Na₂SO₄ andconcentrated in vacuo to give a crude product, which was purified bysilica gel flash chromatography eluting with a 10 to 60% EtOAc-heptanegradient to afford the desired title compound as white foam (11.2 g,66.3%). MS: 416.1 (M+H⁺).

[B] (rac)-4-[1-[1-[(4-Methoxyphenyl)methyl]pyrazol-3-yl]ethyl]piperidine

To a stirred solution of (rac)-tert-butyl4-[1-hydroxy-1-[1-[(4-methoxyphenyl)methyl]-pyrazol-3-yl]ethyl]piperidine-1-carboxylate(11 g, 26.5 mmol) in DCM (10 mL) was added triethylsilane (15 mL) and2,2,2-trifluoroacetic acid (20 mL) at 0° C. The resulting mixture wasallowed to warm up to room temperature and stirred for 4 h. The reactionmixture was then concentrated in vacuo to give a crude product as yellowoil (7.95 g, 100%). MS: 300.1 (M+H⁺). It was used in the next stepwithout further purification.

[C] (rac)-tert-Butyl4-[1-[1-[(4-methoxyphenyl)methyl]pyrazol-3-yl]ethyl]piperidine-1-carboxylate

To a stirred solution of(rac)-4-[1-[1-[(4-methoxyphenyl)methyl]pyrazol-3-yl]ethyl]-piperidine(26.5 mmol) and DIEPA (10 mL) in DCM (70 mL) was added (Boc)₂O (8.4 g,38.8 mmol) at 0° C. The resulting mixture was stirred at roomtemperature for 1 h before it was poured into satd. aq. NaCl (40 mL).The aqueous layer was extracted with diethyl ether (2×100 mL) and thecombined organics were washed with brine (200 mL), dried over anhy.Na₂SO₄ and concentrated in vacuo to give a crude product, which waspurified by silica gel flash chromatography eluting with a 0 to 50%EtOAc-heptane gradient to afford the desired title compound as yellowoil (9.5 g, 93.3%). MS: 400.1 (M+H⁺).

[D](rac)-4-[1-[4-Iodo-1-[(4-methoxyphenyl)methyl]pyrazol-3-yl]ethyl]piperidine

To a stirred solution of (rac)-tert-butyl4-[1-[1-[(4-methoxyphenyl)methyl]pyrazol-3-yl]-ethyl]piperidine-1-carboxylate(4 g, 10 mmol) in HOAc (32 mL) was added a solution of ICl (1 M in HOAc,11 mL, 11 mmol) in HOAc (8 mL) slowly at room temperature followed bythe addition of 4 mL of H₂O. The resulting solution was then heated to85° C. for 10 h. After cooling to room temperature, the reaction mixturewas concentrated in vacuo to give a crude product as yellow oil (1.6 g,37.6%). MS: 426.1 (M+H⁺). It was used in the next step without furtherpurification.

[E](rac)-1-[4-[1-[4-Iodo-1-[(4-methoxyphenyl)methyl]pyrazol-3-yl]ethyl]-1-piperidyl]ethanone

To a stirred solution of(rac)-4-[1-[4-iodo-1-[(4-methoxyphenyl)methyl]pyrazol-3-yl]-ethyl]piperidine(800 mg, 2 mmol) and Et₃N (0.50 mL) in DCM (10 mL) was added acetylchloride (0.2 mL, 3 mmol) at 0° C. and stirring was continued at 0° C.for 1 h. The resulting mixture was extracted with EtOAc (2×100 mL) andthe combined organics were washed with brine, dried over anhy. Na₂SO₄,filtered and concentrated in vacuo to give a crude product, which waspurified by silica gel flash chromatography eluting with a 0 to 50%EtOAc-heptane gradient to afford the desired title compound as yellowoil (630 mg, 67.5%). MS: 468.1 (M+H⁺).

[F](rac)-6-[3-[1-(1-Acetyl-4-piperidyl)ethyl]-1-[(4-methoxyphenyl)methyl]pyrazol-4-yl]-7-fluoro-1-methyl-3,4-dihydroquinolin-2-one

To a stirred solution of(rac)-1-[4-[1-[4-iodo-1-[(4-methoxyphenyl)methyl]pyrazol-3-yl]ethyl]-1-piperidyl]ethanone(200 mg, 0.43 mmol) in dioxane/H₂O (6:1, 7 mL) was added7-fluoro-1-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydroquinolin-2-one(intermediate A-4, 144 mg, 0.473 mmol), Cs₂CO₃ (280 mg, 0.856 mmol) andPdCl₂(DPPF)—CH₂Cl₂ (20 mg). The resulting mixture was stirred at 100° C.for 3 h before it was poured into satd. aq. NaCl (20 mL). The aqueouslayer was extracted with EtOAc (2×60 mL) and the combined organics werewashed with brine (30 mL), dried over anhy. Na₂SO₄ and concentrated invacuo to give a crude product, which was purified by silica gel flashchromatography eluting with a 0 to 30% methanol-DCM gradient to affordthe desired title compound as yellow oil (130 mg, 58.5%). MS: 519.3(M+H⁺).

[G](rac)-6-[4-[1-(1-Acetylpiperidin-4-yl)ethyl]-1H-pyrazol-3-yl]-7-fluoro-1-methyl-3,4-dihydroquinolin-2-one

In a microwave vial,(rac)-6-[3-[1-(1-acetyl-4-piperidyl)ethyl]-1-[(4-methoxyphenyl)-methyl]pyrazol-4-yl]-7-fluoro-1-methyl-3,4-dihydroquinolin-2-one(130 mg) in 2,2,2-trifluoroacetic acid (5 mL) was heated to 150° C. for30 min under microwave irradiation. After cooling to room temperature,it was concentrated in vacuo to give a crude product, which was purifiedby prep-HPLC to afford the desired title compound as white foam (19 mg,19.2%). MS: 399.1 (M+H⁺).

Example 36(rac)-6-[4-[1-(1-Acetylpiperidin-4-yl)ethyl]-1H-pyrazol-3-yl]-5-fluoro-1-methyl-3,4-dihydroquinolin-2-one

[A](rac)-6-[3-[1-(1-Acetyl-4-piperidyl)ethyl]-1-[(4-methoxyphenyl)methyl]pyrazol-4-yl]-5-fluoro-1-methyl-3,4-dihydroquinolin-2-one

In analogy to the procedure described for the synthesis of example35[F],5-fluoro-1-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydroquinolin-2-one(intermediate A-6) was used to give desired title compound as yellow oil(540 mg, 92.1%). MS: 519.3 (M+H⁺).

[B](rac)-6-[4-[1-(1-Acetylpiperidin-4-yl)ethyl]-1H-pyrazol-3-yl]-5-fluoro-1-methyl-3,4-dihydroquinolin-2-one

In analogy to the procedure described for the synthesis of example35[G],(rac)-6-[3-[1-(1-acetyl-4-piperidyl)ethyl]-1-[(4-methoxyphenyl)methyl]pyrazol-4-yl]-5-fluoro-1-methyl-3,4-dihydroquinolin-2-onewas used to give the desired title compound as white foam (90 mg,22.2%). MS: 399.1 (M+H⁺).

Example 37 and Example 38 (−)-6-[4-[(1S or1R)-1-(1-Acetylpiperidin-4-yl)ethyl]-1H-pyrazol-3-yl]-5-fluoro-1-methyl-3,4-dihydroquinolin-2-oneand (+)-6-[4-[(1R or1S)-1-(1-acetylpiperidin-4-yl)ethyl]-1H-pyrazol-3-yl]-5-fluoro-1-methyl-3,4-dihydroquinolin-2-one

The title compounds were prepared by chiral separation of(rac)-6-[4-[1-(1-acetylpiperidin-4-yl)ethyl]-1H-pyrazol-3-yl]-5-fluoro-1-methyl-3,4-dihydroquinolin-2-one(Example 36, 80 mg) on a SFC-minigram AD-H column (CO₂/ethanol, 60:40)to give (−)-6-[4-[(1S or1R)-1-(1-acetylpiperidin-4-yl)ethyl]-1H-pyrazol-3-yl]-5-fluoro-1-methyl-3,4-dihydroquinolin-2-one(example 37, 10 mg, 25%), MS: 399.1 (M+H⁺) and (+)-6-[4-[(1R or1S)-1-(1-acetylpiperidin-4-yl)ethyl]-1H-pyrazol-3-yl]-5-fluoro-1-methyl-3,4-dihydroquinolin-2-one(example 38, 12.5 mg, 31.2%) as off-white foams. MS: 399.1 (M+H⁺).

Example 395-Chloro-6-[4-[(2-ethylsulfonyl-2-azaspiro[3.3]heptan-6-yl)methyl]-1H-pyrazol-3-yl]-1-methyl-3,4-dihydroquinolin-2-one

[A] (rac)-tert-butyl6-[hydroxy-(1-tetrahydropyran-2-ylpyrazol-4-yl)methyl]-2-azaspiro[3.3]heptane-2-carboxylate

To a stirred solution of (rac)-4-iodo-1-tetrahydropyran-2-yl-pyrazole(3.4 g, 12.2 mmol, Intermediate A-9[A]) in THF (30 mL) was added iPrMgCl(1.3 M in THF, 13.4 mmol) drop wise at 0° C. After the addition, thereaction mixture was allowed to warm up to room temperature and stirredfor 1 h before tert-butyl 6-formyl-2-azaspiro[3.3]heptane-2-carboxylate(3.6 g, 13.4 mmol) in THF (10 mL) was added drop wise. The resultingreaction mixture was stirred at room temperature overnight before it waspoured into a satd. aq. NH₄Cl solution. The aqueous layer was extractedwith EtOAc and the combined organics were washed with brine, dried overanhy. Na₂SO₄ and concentrated in vacuo. The crude product was purifiedby silica gel flash chromatography (DCM:MeOH=10:1) to give the desiredtitle compound (3.4 g, 72.3%) as a yellow solid. MS: 378.1 [M+H⁺].

[C] 6-(1H-pyrazol-4-ylmethyl)-2-azaspiro[3.3]heptane

To a stirred solution of (rac)-tert-butyl6-[hydroxy-(1-tetrahydropyran-2-ylpyrazol-4-yl)methyl]-2-azaspiro[3.3]heptane-2-carboxylate(3.4 g, 9.0 mmol) in Et₃SiH (30 mL) was added TFA (40 mL) drop wise at0° C. The resulting mixture was slowly warmed up to room temperature andstirred for additional 12 h. After evaporation of the solvents, a crudeproduct was obtained as colorless oil (2.0 g, 100%). MS: 178.1 [M+H⁺].It was used in the next step without further purification.

[D] tert-Butyl6-(1H-pyrazol-4-ylmethyl)-2-azaspiro[3.3]heptane-2-carboxylate

To a stirred solution of6-(1H-pyrazol-4-ylmethyl)-2-azaspiro[3.3]heptane (2 g, crude, 9 mmol),DIEPA (5 mL) in DCM (30 mL) was added tert-butoxycarbonyl tert-butylcarbonate (1.9 g, 9 mmol) portion wise at 0° C. The mixture was slowlywarmed up to room temperature and stirred for 2 h before washed withsatd. aq. NaHCO₃ solution and brine. The organic layer was dried overanhy. Na₂SO₄, filtered, and concentrated in vacuo to give a crudeproduct, which was purified by silica gel flash chromatography(hexane:EA=3:1) to afford the desired title compound as colorless oil(2.0 g, 80%). MS: 278.1 [M+H⁺].

[E] tert-Butyl6-[(3-iodo-1H-pyrazol-4-yl)methyl]-2-azaspiro[3.3]heptane-2-carboxylate

To a stirred solution of tert-butyl6-(1H-pyrazol-4-ylmethyl)-2-azaspiro[3.3]heptane-2-carboxylate (1.4 g,5.1 mmol) in DMF (4 mL) was added NIS (1.15 g, 5.1 mmol) portion wise atroom temperature. The reaction mixture was stirred at room temperaturefor additional 8 h. It was then diluted with EtOAc (50 mL), washed withsatd. aq. Na₂S₂O₄ solution (2×20 mL) and brine (2×20 mL). The combinedorganic layers were dried over anhy. Na₂SO₄, filtered, and concentratedin vacuo to give a crude product, which was purified by silica gel flashchromatography (hexane:EA=3:1) to afford the desired title compound asyellow oil (1.2 g, 60%). MS: 404.1 [M+H⁺].

[F] tert-Butyl6-[[3-(5-chloro-1-methyl-2-oxo-3,4-dihydroquinolin-6-yl)-1H-pyrazol-4-yl]methyl]-2-azaspiro[3.3]heptane-2-carboxylate

To a stirred solution of tert-butyl6-[(3-iodo-1H-pyrazol-4-yl)methyl]-2-azaspiro[3.3]heptane-2-carboxylate(200 mg, 0.5 mmol), Cs₂CO₃ (325 mg, 1 mmol) and5-chloro-1-methyl-6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,4-dihydro-1H-quinolin-2-one(178 mg, 0.55 mmol) (intermediate A-7) in dioxane/H₂O (5:1, 5 mL) wasadded PdCl₂(DPPF)—CH₂Cl₂ (20 mg) under N₂. The resulting solution washeated to 110° C. for 1 h. After cooling to room temperature, thereaction was quenched with satd. aq. NH₄Cl solution (40 mL), dilutedwith H₂O (50 mL), and extracted with EtOAc (3×20 mL). The combinedorganics were washed with brine (2×20 mL), dried over anhy. Na₂SO₄,filtered, and concentrated in vacuo to give a crude product, which waspurified by silica gel flash chromatography (DCM:MeOH=10:1) to affordthe desired title compound as yellow oil (180 mg, 76.4%). MS: 471.1(M+H⁺).

[G]6-[4-(2-Azaspiro[3.3]heptan-6-ylmethyl)-1H-pyrazol-3-yl]-5-chloro-1-methyl-3,4-dihydroquinolin-2-one

To a stirred solution of tert-butyl6-[[3-(5-chloro-1-methyl-2-oxo-3,4-dihydroquinolin-6-yl)-1H-pyrazol-4-yl]methyl]-2-azaspiro[3.3]heptane-2-carboxylate(180 mg, 0.34 mmol) in DCM (2.0 mL) was added TFA (3 mL) at roomtemperature. The reaction mixture was stirred for 30 min before it wasconcentrated in vacuo to give a crude product as yellow oil (200 mg).MS: 371.1 (M+H⁺). It was used in the subsequent step without furtherpurification.

[H]5-Chloro-6-[4-[(2-ethylsulfonyl-2-azaspiro[3.3]heptan-6-yl)methyl]-1H-pyrazol-3-yl]-1-methyl-3,4-dihydroquinolin-2-one

To a stirred solution of6-[4-(2-azaspiro[3.3]heptan-6-ylmethyl)-1H-pyrazol-3-yl]-5-chloro-1-methyl-3,4-dihydroquinolin-2-one(43 mg, 0.114 mmol) and Et₃N (0.60 mL) in DCM (4 mL) was addedethanesulfonyl chloride (0.016 mL, 0.136 mmol) at 0° C. and stirring wascontinued at 0° C. for 1 h. The resulting mixture was extracted withEtOAc (2×100 mL) and the combined organics were washed with brine, driedover anhy. Na₂SO₄, filtered and concentrated in vacuo to give a crudeproduct, which was purified by pre-HPLC to afford the desired titlecompound as yellow oil (9 mg, 17.1%). MS: 463.1 (M+H⁺).

Example 406-[4-[(2-Acetyl-2-azaspiro[3.3]heptan-6-yl)methyl]-1H-pyrazol-3-yl]-5-chloro-1-methyl-3,4-dihydroquinolin-2-one

To a stirred solution of6-[4-(2-azaspiro[3.3]heptan-6-ylmethyl)-1H-pyrazol-3-yl]-5-chloro-1-methyl-3,4-dihydroquinolin-2-one(example 39[G], 43 mg, 0.114 mmol) and Et₃N (0.60 mL) in DCM (4 mL) wasadded acetyl chloride (10.7 mg, 0.136 mmol) at 0° C. and stirring wascontinued at 0° C. for 1 h. The resulting mixture was extracted withEtOAc (2×100 mL) and the combined organics were washed with brine, driedover anhy. Na₂SO₄, filtered and concentrated in vacuo to give a crudeproduct, which was purified by pre-HPLC to afford the desired titlecompound as yellow oil (6 mg, 12.7%). MS: 413.2 (M+H⁺).

Example 415-Chloro-1-methyl-6-[4-[[2-(1-methylpyrazole-4-carbonyl)-2-azaspiro[3.3]heptan-6-yl]methyl]-1H-pyrazol-3-yl]-3,4-dihydroquinolin-2-one

To a stirred solution of6-[4-(2-azaspiro[3.3]heptan-6-ylmethyl)-1H-pyrazol-3-yl]-5-chloro-1-methyl-3,4-dihydroquinolin-2-one(example 39[G], 43 mg, 0.114 mmol), HATU (20 mg, 0.145 mmol) and Et₃N(0.60 mL) in DCM (4 mL) was added 1-methylpyrazole-4-carboxylic acid(63.5 mg, 0.21 mmol) at 0° C. and stirring was continued at roomtemperature for 1 h. The resulting mixture was extracted with EtOAc(2×50 mL) and the combined organics were washed with brine, dried overanhy. Na₂SO₄, filtered and concentrated in vacuo to give a crudeproduct, which was purified by pre-HPLC to afford the desired titlecompound as yellow oil (9 mg, 16.5%). MS: 479.2 (M+H⁺).

Example A

A compound of formula (I) can be used in a manner known per se as theactive ingredient for the production of tablets of the followingcomposition:

Per tablet Active ingredient 200 mg Microcrystalline cellulose 155 mgCorn starch  25 mg Talc  25 mg Hydroxypropylmethyl cellulose  20 mg 425mg

Example B

A compound of formula (I) can be used in a manner known per se as theactive ingredient for the production of capsules of the followingcomposition:

Per capsule Active ingredient 100.0 mg  Corn starch 20.0 mg Lactose 95.0mg Talc  4.5 mg Magnesium stearate  0.5 mg 220.0 mg 

We claim:
 1. A compound of formula (I)

wherein: R¹, R⁵, R⁶, R⁷ and R⁸ in each occurrence are independentlyselected from H, alkyl, haloalkyl, cycloalkyl and halocycloalkyl; R², R³and R⁴ in each occurrence are independently selected from H, halogen,alkyl, haloalkyl, cycloalkyl and halocycloalkyl; R⁹, R¹², R¹³, R¹⁶ andR¹⁷ in each occurrence are (i) independently selected from H, alkyl andcycloalkyl, and, R¹¹ together with R¹⁴ form —CH₂CH₂—, or, (ii) R⁹, R¹⁶and R¹⁷ in each occurrence are independently selected from H, alkyl andcycloalkyl and R¹² together with R¹¹ and R¹³ together with R¹⁴ both form—CH₂; R¹⁰ is alkyl, aryl, substituted aryl, arylalkyl, substitutedarylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl orsubstituted heteroarylalkyl, wherein substituted aryl, substitutedarylalkyl, substituted heteroaryl and substituted heteroarylalkyl aresubstituted with one to three substituents selected from alkyl, halogen,haloalkyl, cycloalkyl, halocycloalkyl, cyano, alkoxy, haloalkoxy,alkylsulfanyl, haloalkylsulfanyl, alkylsulfonyl and haloalkylsulfonyl; Ais —C(O)— or —S(O)₂— n is zero or 1; m is 1; or, pharmaceuticallyacceptable salts thereof.
 2. The compound according to claim 1, whereinR¹ is alkyl.
 3. The compound according to claim 1 wherein R⁵, R⁶, R⁷ andR⁸ are H.
 4. The compound according to claim 1 wherein R² is H.
 5. Thecompound according to claim 1 wherein one of R³ and R⁴ is H and theother one is halogen.
 6. The compound according to claim 1 wherein R³and R⁴ are H.
 7. The compound according to claim 1 wherein R¹⁶ is H oralkyl.
 8. The compound according to claim 1 wherein R⁹, R¹², R¹³ and R¹⁷are H.
 9. The compound according to claim 1 wherein R⁹, R¹², R¹³, R¹⁶and R¹⁷ are H.
 10. The compound according to claim 1 wherein n is
 1. 11.The compound according to claim 1 wherein A is —C(O)—.
 12. The compoundaccording to claim 1 wherein R⁹, R¹², R¹³, R¹⁶ and R¹⁷ in eachoccurrence are independently selected from H, alkyl and cycloalkyl, and,R¹¹ together with R¹⁴ form —CH₂CH₂—,
 13. The compound according to claim1 wherein R⁹, R¹⁶ and R¹⁷ in each occurrence are independently selectedfrom H, alkyl and cycloalkyl and R¹² together with R¹¹ and R¹³ togetherwith R¹⁴ both form —CH₂;
 14. The compound according to claim 1 whereinR¹⁰ is alkyl or heteroaryl substituted with one to three substituentsselected from alkyl, halogen, cyano, alkoxy, alkylsulfanyl andalkylsulfonyl.
 15. The compound according to claim 14 wherein R¹⁰ isalkyl or substituted pyrazolyl, substituted imidazolyl or substitutedpyridinyl.
 16. The compound according to claim 15, wherein R¹⁰ is alkylor substituted pyrazolyl, substituted imidazolyl or substitutedpyridinyl, wherein substituted pyrazolyl, substituted imidazolyl andsubstituted pyridinyl are substituted with one alkyl or one halogen. 17.The compound according to claim 16 wherein R¹⁰ is substituted pyrazolyl,substituted imidazolyl or substituted pyridinyl.
 18. The compoundaccording to claim 1 which compound is selected from the groupconsisting of:6-[4-[(1-Acetyl-4-piperidyl)methyl]-1H-pyrazol-3-yl]-1-methyl-3,4-dihydroquinolin-2-one;1-Methyl-6-[4-[[1-(1-methylpyrazole-4-carbonyl)-4-piperidyl]methyl]-1H-pyrazol-3-yl]-3,4-dihydroquinolin-2-one;6-[4-[(1-Ethylsulfonyl-4-piperidyl)methyl]-1H-pyrazol-3-yl]-1-methyl-3,4-dihydroquinolin-2-one;6-[4-[(1-Acetylpiperidin-4-yl)methyl]-1H-pyrazol-3-yl]-7-fluoro-1-methyl-3,4-dihydroquinolin-2-one;5-Fluoro-1-methyl-6-[4-[[1-(1-methylpyrazole-4-carbonyl)piperidin-4-yl]methyl]-1H-pyrazol-3-yl]-3,4-dihydroquinolin-2-one;6-[4-[(1-Acetylpiperidin-4-yl)methyl]-1H-pyrazol-3-yl]-5-fluoro-1-methyl-3,4-dihydroquinolin-2-one;6-[4-[(1-Ethylsulfonylpiperidin-4-yl)methyl]-1H-pyrazol-3-yl]-5-fluoro-1-methyl-3,4-dihydroquinolin-2-one;5-Fluoro-1-methyl-6-[4-[[1-(2-methylpyrazole-3-carbonyl)piperidin-4-yl]methyl]-1H-pyrazol-3-yl]-3,4-dihydroquinolin-2-one;5-Fluoro-1-methyl-6-[4-[[1-(1-methylimidazole-2-carbonyl)piperidin-4-yl]methyl]-1H-pyrazol-3-yl]-3,4-dihydroquinolin-2-one;6-[4-[(1-Acetylpiperidin-4-yl)methyl]-1H-pyrazol-3-yl]-5-chloro-1-methyl-3,4-dihydroquinolin-2-one;1-Methyl-6-[4-[[1-(2-methylpyrazole-3-carbonyl)-4-piperidyl]methyl]-1H-pyrazol-3-yl]-3,4-dihydroquinolin-2-one;5-Chloro-1-methyl-6-[4-[[1-(1-methylpyrazole-4-carbonyl)-4-piperidyl]methyl]-1H-pyrazol-3-yl]-3,4-dihydroquinolin-2-one;5-Chloro-6-[4-[[1-(3-chloropyridine-2-carbonyl)-4-piperidyl]methyl]-1H-pyrazol-3-yl]-1-methyl-3,4-dihydroquinolin-2-one;5-Chloro-1-methyl-6-[4-[[1-(2-methylpyrazole-3-carbonyl)-4-piperidyl]methyl]-1H-pyrazol-3-yl]-3,4-dihydroquinolin-2-one;5-Chloro-6-[4-[[1-(3-chloropyridine-4-carbonyl)-4-piperidyl]methyl]-1H-pyrazol-3-yl]-1-methyl-3,4-dihydroquinolin-2-one;1-Methyl-6-[4-[[1-(3-methylimidazole-4-carbonyl)-4-piperidyl]methyl]-1H-pyrazol-3-yl]-3,4-dihydroquinolin-2-one;1-Methyl-6-[4-[[1-(1-methylimidazole-2-carbonyl)-4-piperidyl]methyl]-1H-pyrazol-3-yl]-3,4-dihydroquinolin-2-one;1-Methyl-6-[4-[[1-(4-methylpyridine-3-carbonyl)-4-piperidyl]methyl]-1H-pyrazol-3-yl]-3,4-dihydroquinolin-2-one;6-[4-[[1-(3-Chloropyridine-2-carbonyl)-4-piperidyl]methyl]-1H-pyrazol-3-yl]-1-methyl-3,4-dihydroquinolin-2-one;(rac)-6-[4-[1-(1-Acetylpiperidin-4-yl)ethyl]-1H-pyrazol-3-yl]-7-fluoro-1-methyl-3,4-dihydroquinolin-2-one;(rac)-6-[4-[1-(1-Acetylpiperidin-4-yl)ethyl]-1H-pyrazol-3-yl]-5-fluoro-1-methyl-3,4-dihydroquinolin-2-one;6-[4-[(1S or1R)-1-(1-Acetylpiperidin-4-yl)ethyl]-1H-pyrazol-3-yl]-5-fluoro-1-methyl-3,4-dihydroquinolin-2-one;6-[4-[(1R or1S)-1-(1-Acetylpiperidin-4-yl)ethyl]-1H-pyrazol-3-yl]-5-fluoro-1-methyl-3,4-dihydroquinolin-2-one;5-Chloro-6-[4-[(2-ethylsulfonyl-2-azaspiro[3.3]heptan-6-yl)methyl]-1H-pyrazol-3-yl]-1-methyl-3,4-dihydroquinolin-2-one;6-[4-[(2-Acetyl-2-azaspiro[3.3]heptan-6-yl)methyl]-1H-pyrazol-3-yl]-5-chloro-1-methyl-3,4-dihydroquinolin-2-one;and,5-Chloro-1-methyl-6-[4-[[2-(1-methylpyrazole-4-carbonyl)-2-azaspiro[3.3]heptan-6-yl]methyl]-1H-pyrazol-3-yl]-3,4-dihydroquinolin-2-one;or, a pharmaceutically acceptable salts thereof.
 19. A process toprepare a compound according to claim 1 comprising the reaction of acompound of formula (II) in the presence of a compound of formula (III);

wherein R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹², R¹³, R¹⁴,R¹⁵, R¹⁶, R¹⁷, m and n are wherein R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹,R¹⁰, R¹¹, R¹², R¹³, R¹⁴, R¹⁵, R¹⁶, R¹⁷, m and n are as defined in claim1 and X and X is halogen or hydroxy.
 20. A pharmaceutical compositioncomprising a compound according to claim 1 and at least onepharmaceutically acceptable carrier, diluent or excipient.
 21. A methodfor the treatment of chronic kidney disease, congestive heart failure,hypertension, primary aldosteronism and Cushing syndrome, which methodcomprises administering to a patient in need thereof, an therapeuticallyeffective amount of a compound according claim 1.